Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes

ABSTRACT

The present invention provides novel substituted amino-azetidines that are useful as cannabinoid receptor antagonists/inverse agonists and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, dyslipidemias, cardiovascular disorders, hepatic disorders, and a combination thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority benefit under 35 U.S.C. §119(e)of U.S. Provisional Patent Application Ser. No. 61/025,082 filed 31 Jan.2008. The disclosure this application is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention provides cannabinoid receptor antagonists/inverseagonists and pharmaceutical compositions thereof and methods of usingthe same for treating obesity, diabetes, dyslipidemias, cardiovasculardisorders, and/or hepatic disorders. More particularly, the presentinvention relates to a novel method for treating obesity, diabetes,dyslipidemias, cardiovascular disorders and/or hepatic disorders using asubstituted amino-azetidine.

BACKGROUND OF THE INVENTION

Obesity is associated with an increase in the overall amount of adiposetissue (i.e., body fat), especially adipose tissue localized in theabdominal area. Obesity has reached epidemic proportions in the UnitedStates. The prevalence of obesity has steadily increased over the yearsamong all racial and ethnic groups. The most recent data from theCenters for Disease Control and Prevention, and the National Center forHealth Statistics report 66% of the adult population overweight (BMI,25.0-29.9), 31% obese (BMI, 30-39.9), and 5% extremely obese(BMI, >40.0). Among children aged 6 through 19 years, 32% wereoverweight and 17% were obese. This translates to 124 million Americansmedically overweight, and 44 million of these deemed obese. Obesity isresponsible for more than 300,000 deaths annually, and will soonovertake tobacco usage as the primary cause of preventable death in theUnited States. Obesity is a chronic disease that contributes directly tonumerous dangerous co-morbidities, including type 2 diabetes,cardiometabolic diseases, hepatic disorders, cardiovascular disease,inflammatory diseases, premature aging, and some forms of cancer. Type 2diabetes, a serious and life-threatening disorder with growingprevalence in both adult and childhood populations, is currently the7^(th) leading cause of death in the United States. Since more than 80%of patients with type 2 diabetes are overweight, obesity is the greatestrisk factor for developing type 2 diabetes. Increasing clinical evidenceindicates that the best way to control type 2 diabetes is to reduceweight.

The most popular over-the counter drugs for the treatment of obesity,phenylpropanolamine and ephedrine, and the most popular prescriptiondrug, fenfluramine, were removed from the marketplace as a result ofsafety concerns. Drugs currently approved for the long-term treatment ofobesity fall into two categories: (a) CNS appetite suppressants such assibutramine and rimonabant, and (b) gut lipase inhibitors such asorlistat. CNS appetite suppressants reduce eating behavior throughactivation of the ‘satiety center’ in the brain and/or by inhibition ofthe ‘hunger center’ in the brain. Gut lipase inhibitors reduce theabsorption of dietary fat from the gastrointestinal (GI) tract. Althoughappetite suppressants and gut lipase inhibitors work through verydifferent mechanisms, they share in common the same overall goal ofreducing body weight secondary to reducing the amount of calories thatreach the systemic circulation. Unfortunately, these indirect therapiesproduce only a modest initial weight loss (approximately 5% compared toplacebo) that is usually not maintained. After one or two years oftreatment, most patients return to or exceed their starting weight. Inaddition, most approved anti-obesity therapeutics produce undesirableand often dangerous side effects that can complicate treatment andinterfere with a patient's quality of life.

The lack of therapeutic effectiveness, coupled with the spiralingobesity epidemic, positions the ‘treatment of obesity’ as one of thelargest and most urgent unmet medical needs. There is, therefore, a realand continuing need for the development of improved medications thattreat or prevent obesity.

The endocanabinoid system, comprised of the canabinoid receptors (CB1and CB2) and their endogenous ligands (e.g., anandamide, 2-AG), plays aprominent role in the control of food intake and energy metabolism. CB1receptors are widely expressed in the brain, including cortex,hippocampus, amygdala, pituitary and hypothalamus. CB1 receptors havealso been identified in numerous peripheral organs and tissues,including thyroid gland, adrenal gland, reproductive organs, adiposetissue, liver, muscle, pancreas, and gastrointestinal tract. CB2receptors are localized almost exclusively in immune and blood cells[Endocrine Reviews 2006, 27, 73].

The plant-derived cannabinoid agonist Δ⁹-tetrahydrocannabinol (Δ⁹-THC),the main psychoactive component of marijuana, binds to both CB1 and CB2receptors. Δ⁹-THC is widely reported to increase appetite and foodintake (hyperphagia) in humans and in animals. This hyperphagic effectis largely blocked by pretreatment with selective CB1 receptor blockers(i.e., CB1 blockers) (e.g., rimonabant (SR141716A, Acomplia®)), stronglysupporting the belief that CB1 receptor activation mediates thehyperphagic effect of Δ⁹-THC, [Endocrine Reviews 2006, 27, 73].

In humans, rimonabant produces a clinically meaningful weight loss inobese patients. Obese patients also experience improvements in diabeticand cardiometabolic risk factors associated with obesity, including anincrease in the level of high density lipoprotein cholesterol (HDL), anddecreases in triglycerides, glucose, and hemoglobin Alc (HbAlc, a markerof cumulative exposure to glucose) levels. Rimonabant also producesgreater reductions in abdominal fat deposits, which are a known riskfactor for diabetes and heart disease [Science 2006, 311, 323]. Takentogether, these improvements in adiposity and cardiometabolic riskfactors produce an overall decrease in the prevalence of the metabolicsyndrome [Lancet 2005, 365, 1389 and NEJM 2005, 353, 2121].

In patients with type 2 diabetes not currently treated with otheranti-diabetic medications, rimonabant was shown to significantly improveblood sugar control and weight, as well as other risk factors such asHDL and triglycerides, when compared to placebo (International DiabetesFederation World Diabetes Congress, Cape Town, South Africa, 2006).After six months of treatment, HbA1c levels were significantly loweredby 0.8% from a baseline value of 7.9 as compared to a reduction of 0.3%in the placebo group. These results are consistent with preclinicalstudies that demonstrate improved glycemic and lipid control in diabeticand dyslipedemic mice, rats, and dogs (Pharmacology Biochemistry &Behavior, 2006, 84, 353; American Journal of Physiology, 2003, 284,R345; American Diabetes Association Annual Meeting, 2007; AbstractNumber 0372-OR).

The beneficial effects of rimonabant on diabetic and cardiometabolicrisk factors such as high blood pressure, insulin resistance, andeleveated triglycerides cannot be explained by diet-related weight lossalone. For example, in patients receiving 20 mg of rimonabant, onlyapproximately 50% of the beneficial effects on triglycerides, fastinginsulin, and insulin resistance can be accounted for by weight losssecondary to reduced food intake. These results suggest a directpharmacological effect of CB1 antagonists on glucose and lipidmetabolism, in addition to indirect effects on metabolism secondary tohypophagia-mediated weight loss [Science 2006, 311, 323 and JAMA 2006,311, 323]. Taken together, these results suggest that CB1 antagonistsmight be effective in the treatment of diabetes, dyslipidemias,cardiovascular disorders (e.g., atherosclerosis, hypertension), andhepatic disorders (e.g., cirrhosis, fatty liver diseases), even inpatients that are not clinically overweight or obese.

The CB1 receptor is one of the most abundant and widely distributed Gprotein-coupled receptors in the mammalian brain. It is believed thatthe appetite-suppressant properties of CB1 antagonists are mediatedthrough an interaction with CB1 receptors in the hypothalamus(regulation of food intake), and in the mesolimbic region (rewardingproperties of food). However, CB1 receptors are far more broadlydistributed in brain (e.g., neocortex, hippocampus, thalamus,cerebellum, and pituitary), and while interacting with targeted CB1receptors in hypothalamus and mesolimbic regions to suppress appetite,CB1 antagonists have equal access to non-targeted CB1 receptors thathave little if any role in appetite control. Binding to non-targetedreceptors can often lead to unwanted side effects of CNS drugs[Endocrine Reviews 2006, 27: 73]. The CB1 blockers rimonabant andtaranabant produce psychiatric and neurological side effects. Theseinclude depressed mood, anxiety, irritability, insomnia, dizziness,headache, seizures, and suicidality.

These side effects are dose-related and appear pronounced at the mostefficacious weight-reducing doses of rimonabant and taranabant (JAMA2006, 311, 323; Cell Metabolism 2008, 7, 68). The occurrence oftherapeutic efficacy (appetite suppression) and side effects over thesame dose range strongly suggest that both effects are mediated throughconcurrent antagonism of CB1 receptors in both ‘targeted’ and‘non-targeted’ brain regions. Brain-penetrant CB1 blockers do notselectively target CB1 receptors in efficacy brain regions, whileignoring CB1 receptors in side effect brain regions.

The beneficial effects of the CB1 antagonist rimonabant on body weight,adiposity, and diabetic and cardiometabolic risk factors such as highblood pressure, insulin resistance and blood lipids cannot be explainedby weight loss derived from CNS-mediated appetite suppression alone[JAMA 2006, 311, 323]. Approximately 50% of the benefit is likelyderived from an interaction with CB1 receptors in peripheral tissuesknown to play an active role in metabolism. These include adiposetissue, liver, muscle, pancreas, and gastrointestinal tract.

U.S. Pat. Nos. 6,355,631 and 6,734,176 describe azetidine cannabinoidreceptor antagonists of formula A:

wherein R₁ is a substituted amino group. Neither of these patentsdiscusses nor considers limiting the CNS side effects of the describedazetidine compounds. The compounds of these patents are not consideredto be part of the present invention.

In view of the above, it is highly desirable to find effective andhighly selective CB1 receptor blockers with limited or no CNS adverseside effects, including mood disorders. Particularly, it is desirable tofind compounds that preferentially target CB1 receptors in peripheraltissues (e.g., adipose tissue, liver, muscle, pancreas, andgastrointestinal tract), while sparing CB1 receptors in brain. In thisway, peripherally-mediated beneficial effects of CB1 blockers should bemaintained, whereas CNS side effects should be reduced or eliminated.This should provide a novel opportunity to develop safer alternatives tohighly brain penetrant CB1 blockers for the prevention or treatment ofobesity, diabetes, dyslipidemias, cardiovascular disorders, and/orhepatic disorders.

SUMMARY OF THE INVENTION

Accordingly, in an aspect, the present invention provides novelsubstituted amino-azetidines or pharmaceutically acceptable saltsthereof that are CB1 receptor antagonists/inverse agonists.

In another aspect, the present invention provides novel pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another aspect, the present invention provides novel methods fortreating obesity, diabetes (e.g., insulin resistance, inadequate glucosetolerance, Type I diabetes, and Type II diabetes), dyslipidemias (e.g.,elevated triglyerides and LDL, and low HDL), cardiovascular disorders(e.g., atherosclerosis and hypertension), and/or hepatic disorders(e.g., nonalcoholic steatohepatitis (NASH), cirrhosis and fatty liverdisease), comprising: administering to a mammal in need of suchtreatment a therapeutically effective amount of at least one of thecompounds of the present invention or a pharmaceutically acceptable saltform thereof.

In another aspect, the present invention provides processes forpreparing novel compounds.

In another aspect, the present invention provides novel compounds orpharmaceutically acceptable salts for use in therapy.

In another aspect, the present invention provides the use of novelcompounds for the manufacture of a medicament for the treatment ofobesity, diabetes, dyslipidemias, cardiovascular disorders, and/orhepatic disorders.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat the presently claimed compounds or pharmaceutically acceptable saltforms thereof are expected to be effective CB1 receptor blockers.

DETAILED DESCRIPTION OF THE INVENTION

All references cited herein are hereby incorporated in their entiretyherein by reference.

A CB1 blocker is a neutral CB1 receptor antagonist and/or a CB1 receptorinverse agonist.

The present invention is based on the finding that a CB1 receptorblocker has beneficial effects on metabolic disorders including obesity,diabetes, dyslipidemias, and cardiovascular and hepatic diseases thatcannot be explained by weight loss derived from CNS-mediated appetitesuppression alone, and that this effect is mediated, at least in part,through interaction at peripheral CB1 receptors. To this end, thepresent invention provides compounds that are designed to preferentiallytarget CB1 receptors in peripheral tissues (e.g., adipose tissue, liver,muscle, pancreas, and gastrointestinal tract), while sparing CB1receptors in brain. With these types of compounds, peripherally-mediatedbeneficial effects of CB1 blockers should be maintained, whereas CNSside effects should be reduced or eliminated.

The compounds of the present invention have been designed to havereduced CNS exposure by virtue of their inability or limited ability topenetrate the blood-brain barrier (BBB), or by their participation inactive transport systems, thus reducing centrally mediated side-effects,a potential problem with many anti-obesity agents. It is expected thatthe peripherally restricted compounds of the present invention will haveno or very limited CNS effects, including mood disorders, seizures, andsuicidality. Thus, their peripherally mediated CB1 blocking propertiesshould provide therapeutic agents with greater safety.

Moreover, if the maximum dosage of a drug used in the treatment ofobesity, diabetes, dyslipidemias, cardiovascular disorders, and/orhepatic disorders is limited as a result of CNS side effects (e.g.,seizures, depression, anxiety, suicidality, movement disorders, andhyperactivity), incorporation of a peripherally restricting group insuch a drug would lower the brain concentration of the drug relative tothe concentration in the systemic circulation, thereby affording theopportunity to increase the dosage employed to treat the peripheraldisorder (e.g., obesity, diabetes, dyslipidemias, cardiovasculardisorders, and/or hepatic disorders). The increased dosage may providegreater therapeutic efficacy, as well as a more rapid onset oftherapeutic action.

In an embodiment, the present invention provides a novel compound AA ora stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

R₁ and R₂ are identical or different, and are either

i) phenyl or naphthyl, optionally substituted with 1-4 substituentsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃,COR₃, —CN, CO₂R₃, CONR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆alkylene-S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-OH, and —C₁₋₆alkylene-NR₄R₅; or

ii) a heteroaryl optionally substituted with 1-4 substituents selectedfrom halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, OH, CF₃, OCF₃, —CN, CO₂R₃,CONR₄R₅, —C₁₋₆ alkylene-NR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆alkylene-S(O)_(p)—C₁₋₆ alkyl, and —C₁₋₆ alkylene-OH;

R₃ is H or C₁₋₆ alkyl;

R₄ and R₅, which are identical or different, are selected from H, OR₃,C₁₋₆ alkyl, CO₂R₃, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, and —C₁₋₆ alkylene-OH;

alternatively, R₄ and R₅ together with the nitrogen atom to which theyare attached form a 3-10-membered saturated mono- or bicyclicheterocycle, optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen and being optionally substituted with 1-4groups selected from C₁₋₆ alkyl, COR₃, CO₂R₃, CONHR₃, CSNHC₁₋₆ alkyl,═O, C₁₋₆ alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, NO₂, NH₂, NHCONH₂,NHC(O)C₁₋₆ alkyl, and —CONH₂;

R₆, at each occurrence, is independently selected from C₁₋₆ alkyl, aryl,C₃₋₈ cycloalkyl, and heterocycle, each of which is optionallysubstituted with 1-4 groups selected from halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, CHO, OH, CF₃, OCF₃, COR₃, —CN, CO₂R₃, and CONR₄R₅;

A is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylene-OH, C₁₋₆alkoxy, —C₁₋₆ alkylene-CO₂R₃, —C₁₋₆ alkylene-NR₄R₅, SO₂R₆, aryl,—CH₂-aryl, heterocycle, and —CH₂-heterocycle;

m, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

alternatively, the azetidine N-atom is an N-oxide when R₁, R₂, R₃, R₄,R₅, R₆, A, and Z do not contain a CO₂R₃ group;

further provided that at least one of R₁, R₂, A, or R₆, or the azetidinering is suitably modified or for R₁, R₂, A, and R₆, replaced, by a groupcapable of reducing or limiting the CNS (brain) levels of compound AA.

[1] In another embodiment, the present invention provides a novelcompound of formula I or Ia or a stereoisomer or pharmaceuticallyacceptable salt thereof:

wherein:

R₁ and R₂ are identical or different, and are either

i) phenyl or naphthyl, optionally substituted with 1-4 substituentsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃,COR_(S), —CN, CO₂R₃, CONR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆alkylene-S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-OH, and —C₁₋₆alkylene-NR₄R₅; or

ii) a heteroaryl optionally substituted with 1-4 substituents selectedfrom halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, OH, CF₃, OCF₃, —CN, CO₂R₃,CONR₄R₅, —C₁₋₆ alkylene-NR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆alkylene-S(O)_(p)—C₁₋₆ alkyl, and —C₁₋₆ alkylene-OH;

R₃ is H or C₁₋₆ alkyl;

R₄ and R₅, which are identical or different, are selected from H, OR₃,C₁₋₆ alkyl, CO₂R₃, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, —C₁₋₆ alkylene-OH, —C₁₋₆alkylene-di-OH, and —C₁₋₆ alkylene-tri-OH;

alternatively, R₄ and R₅ together with the nitrogen atom to which theyare attached form a 3-10-membered saturated mono- or bicyclicheterocycle, optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen and being optionally substituted with 1-4groups selected from C₁₋₆ alkyl, COR₃, CO₂R₃, CONHR₃, CSNHC₁₋₆ alkyl,═O, C₁₋₆ alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, NO₂, NH₂, NHCONH₂,NHC(O)C₁₋₆ alkyl, and —CONH₂;

R₆, at each occurrence, is independently selected from C₁₋₆ alkyl, aryl,C₃₋₈ cycloalkyl, and 5-10 membered heterocycle consisting of: carbonatoms and 1-4 heteroatoms selected from O, S(O)_(q), and N, each ofwhich is optionally substituted with 1-4 groups selected from halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, COR₃, —CN, CO₂R₃, andCONR₄R₅;

A is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylene-OH, C₁₋₆alkoxy, COR_(E), —C₁₋₆ alkylene-CO₂R₃, —C₁₋₆ alkylene-NR₄R₅, SO₂R₆,—C₁₋₆ alkylene-SO₂R₆, CO(C₁₋₄ alkylene-Z)NR₄R₅, SO₂(C₁₋₄alkylene-Z)NR₄R₅, CO(C₁₋₄ alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NR₄R₅, CO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃, CO(C₁₋₄ alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅, CO(C₁₋₄ alkylene-Z)CO(C₁₋₄ alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃, CO(C₁₋₄ alkylene-Z)CO(C₁₋₄ alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅, CO(C₁₋₄ alkylene-Z)SO₂NR₄R₅, CO(C₁₋₄alkylene-Z)SO₂NH(C₁₋₄ alkylene-Z)CO₂R₃, CO(C₁₋₄ alkylene-Z)SO₂NH(C₁₋₄alkylene-Z)CONR₄R₅, SO₂(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃,SO₂(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅, SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NR₄R₅, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)CO₂R₃, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄ alkylene-Z)CONR₄R₅,SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NHCO(CH₂)_(m)CO₂R₃, SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NHCO(CH₂)_(m)CONR₄R₅,SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅,aryl, —CH₂-aryl, heterocycle, and —CH₂-heterocycle, wherein heterocycleis a 5-10 membered heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from O, S(O)_(q), and N;

Z is selected from H, OH, C₁₋₆ alkyl, (CH₂)_(m)-cycloalkyl, aryl,(CH₂)_(m)-aryl, —C₁₋₆ alkylene-OH, —C₁₋₆ alkylene-CO₂R₃, and —C₁₋₆alkylene-CONR₄R₅, wherein the aryl is optionally substituted with 1-4groups selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃,OCF₃, CO—C₁₋₆ alkyl, —CN, CO₂R₃, and CONR₄R₅;

B is selected from H, C₁₋₆ alkyl, —C₁₋₆ alkylene-OH, (CH₂)_(m)CO₂R₃,(CH₂)_(m)CONR₄R₅, (CH₂)_(m)SO₂R₆, ═CHCO₂R₃, ═CHCONR₄R₅, CHOHCO₂R₃,CHOHCONR₄R₅, (CH₂)_(m)CONH(C₁₋₄alkylene-Z)CO₂R₃, (CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONR₄R₅,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)SO₂NR₄R₅,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅,═CHCONH(C₁₋₄alkylene-Z)CO₂R₃, ═CHCONH(C₁₋₄ alkylene-Z)CONR₄R₅,═CHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,═CHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,═CHCONH(C₁₋₄alkylene-Z)SO₂NR₄R₅, CHOHCONH(C₁₋₄alkylene-Z)CO₂R₃,CHOHCONH(C₁₋₄alkylene-Z)CONR₄R₅,CHOHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,CHOHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅, andCHOHCONH(C₁₋₄alkylene-Z)SO₂NR₄R₅,

m, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

q, at each occurrence, is independently selected from 0, 1, and 2;

alternatively, the azetidine N-atom can be an N-oxide or quaternaryammonium salt when R₁, R₂, R₃, R₄, R₅, R₆, A, B and Z do not contain aCO₂R₃ group;

R₇ is selected from O⁻, C₁₋₆-alkyl, C₁₋₆-alkenyl, C₁₋₆-alkynyl, andCH₂-aryl, wherein the aryl is optionally substituted with 1-4 groupsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, OCF₃, —CO—C₁₋₆alkyl, and —CN;

provided that when R₇ is O⁻, X⁻ is absent and when R₇ is other than O⁻,X⁻ is a halogen;

further provided that when B is H, C₁₋₆ alkyl or C₁₋₆ alkylene-OH, thenA is other than H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylene-OH, C₁₋₆alkoxy, (CH₂)_(m)CO₂R₃, —C₁₋₆ alkylene-NR₄R₅, SO₂R₆,CO(C₁₋₄alkylene-Z)NR₄R₅, aryl, CH₂-aryl, heterocycle, andCH₂-heterocycle.

It is noted that C₁₋₄ alkylene-Z is a moiety wherein Z is a substituentoff of any carbon atom of the alkylene chain and is not between thealkylene chain and either group attached to the alkylene chain. Forexample, when Z is OH, the C₁₋₄ alkylene-Z moiety can be —CH(OH)CH₂— or—CH₂CH(OH)—.

[2] In another embodiment, the present invention provides novel compoundof Formula I or a stereoisomer or pharmaceutically acceptable saltthereof:

wherein:

R₁ and R₂ are identical or different, and are either

i) phenyl or naphthyl, optionally substituted with 1-4 substituentsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃,COR₃, —CN, CONR₄R₅, C₁₋₆ alkylene-S(O)_(p)—, C₁₋₆ alkylene-S(O)_(p)—C₁₋₆alkyl, C₁₋₆ alkylene-OH, and —C₁₋₆ alkylene-NR₄R₅; or

ii) a heteroaryl optionally substituted with 1-4 substituents selectedfrom halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, OH, CF₃, OCF₃, —CN, CONR₄R₅,—C₁₋₆ alkylene-NR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-S(O)_(p)—C₁₋₆alkyl, and C₁₋₆ alkylene-OH;

R₃ is H or C₁₋₆ alkyl;

R₄ and R₅, which are identical or different, are selected from H, OR₃,C₁₋₆ alkyl, CO₂R₃, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, and —C₁₋₆ alkylene-OH;

alternatively, R₄ and R₅ together with the nitrogen atom to which theyare attached form a 3-10-membered saturated mono- or bicyclicheterocycle, optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen and being optionally substituted with 1-4groups selected from C₁₋₆ alkyl, COR_(S), CONHC₁₋₆ alkyl, CSNHC₁₋₆alkyl, ═O, C₁₋₆ alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, NO₂, NH₂,NHCONH₂, NHC(O)C₁₋₆ alkyl, and —CONH₂;

R₆, at each occurrence, is independently selected from C₁₋₆ alkyl, aryl,C₃₋₈ cycloalkyl, and a 5-10 membered heterocycle consisting of: carbonatoms and 1-4 heteroatoms selected from O, S(O)_(q), and N, each ofwhich is optionally substituted with 1-4 groups selected from halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, COC₁₋₆ alkyl, —CN, andCONR₄R₅;

A is selected from CO(C₁₋₄alkylene-Z)NR₄R₅, SO₂(C₁₋₄alkylene-Z)NR₄R₅,CO(C₁₋₄ alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NR₄R₅,CO(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃, CO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅, CO(C₁₋₄ alkylene-Z)CO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃, CO(C₁₋₄ alkylene-Z)CO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅, CO(C₁₋₄ alkylene-Z)SO₂NR₄R₅,CO(C₁₋₄ alkylene-Z)SO₂NH(C₁₋₄ alkylene-Z)CO₂R₃, CO(C₁₋₄alkylene-Z)SO₂NH(C₁₋₄ alkylene-Z)CONR₄R₅, SO₂(C₁₋₄ alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃, SO₂(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NR₄R₅, SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄ alkylene-Z)CO₂R₃, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)CONR₄R₅, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)NHCO(CH₂)_(m)CO₂R₃, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)NHCO(CH₂)_(m)CONR₄R₅, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃, and SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,

Z is selected from H, C₁₋₆ alkyl, (CH₂)_(m)-cycloalkyl, aryl,(CH₂)_(m)-aryl, —C₁₋₆ alkylene-OH, —C₁₋₆ alkylene-CO₂R₃, and —C₁₋₆alkylene-CONR₄R₅, wherein the aryl is optionally substituted 1-4 groupsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃,CO—C₁₋₆ alkyl, —CN, CO₂R₃, and CONR₄R₅;

B is selected from H, C₁₋₆ alkyl, and C₁₋₆ alkylene-OH;

m, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and,

p, at each occurrence, is independently selected from 0, 1, and 2.

[3] In another embodiment, the present invention provides novel compoundof Formula I or a stereoisomer or pharmaceutically acceptable saltthereof:

wherein:

R₁ and R₂ are identical or different, and are either

i) phenyl or naphthyl, optionally substituted with 1-4 substituentsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃,COR₃, —CN, CONR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-S(O)_(p)—C₁₋₆alkyl, —C₁₋₆ alkylene-OH, and —C₁₋₆ alkylene-NR₄R₅; or

ii) a heteroaryl optionally substituted with 1-4 substituents selectedfrom halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, OH, CF₃, OCF₃, —CN, CONR₄R₅,-alkylene-NR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-S(O)_(p)—C₁₋₆alkyl, and —C₁₋₆ alkylene-OH;

R₃ is H or C₁₋₆ alkyl;

R₄ and R₅, which are identical or different, are selected from H, OR₃,C₁₋₆ alkyl, CO₂R₃, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, and —C₁₋₆ alkylene-OH;

alternatively, R₄ and R₅ together with the nitrogen atom to which theyare attached form a 3-10-membered saturated mono- or bicyclicheterocycle, optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen and being optionally substituted with 1-4groups selected from C₁₋₆ alkyl, COR₃, CONHC₁₋₆ alkyl, CSNHC₁₋₆ alkyl,═O, —C₁₋₆ alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, NO₂, NH₂, NHCONH₂,NHC(O)C₁₋₆ alkyl, and CONH₂;

R₆, at each occurrence, is independently selected from C₁₋₆ alkyl, aryl,C₃₋₈ cycloalkyl, and a 5-10 membered heterocycle consisting of: carbonatoms and 1-4 heteroatoms selected from O, S(O)_(q), and N, each ofwhich is optionally substituted with 1-4 groups selected from halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, COC₁₋₆ alkyl, —CN, andCONR₄R₅;

A is selected from H, —C₁₋₆ alkylene-OH, C₁₋₆ alkoxy, COR_(E), —C₁₋₆alkylene-NR₄R₅, C₁₋₆ haloalkyl, SO₂R₆, and —C₁₋₆ alkylene-SO₂R₆;

Z is selected from H, C₁₋₆ alkyl, (CH₂)_(m)-cycloalkyl, aryl,(CH₂)_(m)-aryl, —C₁₋₆ alkylene-OH, and —C₁₋₆ alkylene-CONR₄R₅, whereinthe aryl is optionally substituted with 1-4 groups selected fromhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, CO—C₁₋₆ alkyl,—CN, and CONR₄R₅;

B is selected from (CH₂)_(m)CO₂R₃, (CH₂)_(m)CONR₄R₅, ═CHCO₂R₃,═CHCONR₄R₅, CHOHCO₂R₃, CHOHCONR₄R₅, (CH₂)_(m)SO₂R₆, (CH₂)_(m)CONH(C₁₋₄alkylene-Z)CO₂R₃, (CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONR₄R₅,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅,(CH₂)_(m)CONH(C₁₋₄ alkylene-Z)SO₂NR₄R₅,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅, ═CHCONH(C₁₋₄alkylene-Z)CO₂R₃, ═CHCONH(C₁₋₄ alkylene-Z)CONR₄R₅, ═CHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃, ═CHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅, ═CHCONH(C₁₋₄alkylene-Z)SO₂NR₄R₅,CHOHCONH(C₁₋₄alkylene-Z)CO₂R₃, CHOHCONH(C₁₋₄alkylene-Z)CONR₄R₅,CHOHCONH(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃,CHOHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅, andCHOHCONH(C₁₋₄alkylene-Z)SO₂NR₄R₅;

m, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and,

p, at each occurrence, is independently selected from 0, 1, and 2.

[4] In another embodiment, the present invention provides novelcompounds of Formula Ia or a stereoisomer or pharmaceutically acceptablesalt thereof:

wherein:

R₁ and R₂ are identical or different, and are either

i) phenyl or naphthyl, optionally substituted with 1-4 substituentsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃,COR₃, —CN, CONR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-S(O)_(p)—C₁₋₆alkyl, and —C₁₋₆ alkylene-OH; or

ii) a heteroaryl optionally substituted with 1-4 substituents selectedfrom halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, OH, CF₃, OCF₃, —CN, CONR₄R₅,—C₁₋₆ alkylene-NR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-S(O)_(p)—C₁₋₆alkyl, and —C₁₋₆ alkylene-OH;

R₃ is H or C₁₋₆ alkyl;

R₄ and R₅, which are identical or different, are selected from H, OR₃,C₁₋₆ alkyl, CO₂R₃, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, and —C₁₋₆ alkylene-OH;

alternatively, R₄ and R₅ together with the nitrogen atom to which theyare attached form a 3-10-membered saturated mono- or bicyclicheterocycle, optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen and being optionally substituted with 1-4groups selected from C₁₋₆ alkyl, COR₃, CONHC₁₋₆ alkyl, CSNHC₁₋₆ alkyl,═O, C₁₋₆ alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, NO₂, NH₂, NHCONH₂,NHC(O)C₁₋₆ alkyl, and —CONH₂;

R₆, at each occurrence, is independently selected from C₁₋₆ alkyl, aryl,C₃₋₈ cycloalkyl, and a 5-10 membered heterocycle consisting of: carbonatoms and 1-4 heteroatoms selected from O, S(O)_(q), and N, each ofwhich is optionally substituted with 1-4 groups selected from halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, COC₁₋₆ alkyl, —CN, andCONR₄R₅;

A is selected from H, —C₁₋₆ alkylene-OH, C₁₋₆ haloalkyl, COR_(E), SO₂R₆,—C₁₋₆ alkylene-SO₂R₆, CO(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,CO(C₁₋₄ alkylene-Z)CO(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,CO(C₁₋₄ alkylene-Z)SO₂NR₄R₅, CO(C₁₋₄ alkylene-Z)SO₂NH(C₁₋₄alkylene-Z)CONR₄R₅, SO₂(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄ alkylene-Z)CONR₄R₅, SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NHCO(CH₂)_(m)CONR₄R₅, and SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅;

Z is selected from H, C₁₋₆ alkyl, (CH₂)_(m)—C₃₋₈ cycloalkyl, aryl,(CH₂)_(m)-aryl, —C₁₋₆ alkylene-OH, and C₁₋₆ alkylene-CONR₄R₅, whereinthe aryl is optionally substituted with 1-4 groups selected fromhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, CO—C₁₋₆ alkyl,—CN, and CONR₄R₅;

B is selected from H, C₁₋₆ alkyl, C₁₋₆ alkylene-OH; and,

R₇ is selected from O⁻, C₁₋₆-alkyl, C₁₋₆-alkenyl, C₁₋₆-alkynyl, andCH₂-aryl, wherein the aryl is optionally substituted with 1-4 groupsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, OCF₃, —CO—C₁₋₆alkyl, and —CN;

provided that when R₇ is O⁻, X⁻ is absent;

provided that when R₇ is not O⁻, X⁻ is a halogen;

m, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and,

p, at each occurrence, is independently selected from 0, 1, and 2.

In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method ofmodulating the activity of CB1 receptors (e.g., peripheral CB1receptors) in a patient, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method oftreating a disease characterized by an inappropriate activation ofperipheral CB1 receptors, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating a disease mediated by the CB₁ receptor in a patient,comprising: administering to a patient in need thereof a therapeuticallyeffective amount of a compound of the present invention or apharmaceutically acceptable salt form thereof. In an example, thedisease is mediated by peripheral CB₁ receptors. In another example, theCB₁ receptors that are blocked are peripheral CB₁ receptors.

In another embodiment, the present invention provides a novel method fortreating a disease, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt form thereof, whereinthe disease is selected from obesity, diabetes, dyslipidemias,cardiovascular disorders, hepatic disorders, and a combination thereof.

In another embodiment, the diabetes disorder is selected from Type 1diabetes, Type 2 diabetes, inadequate glucose tolerance, and insulinresistance.

In another embodiment, the hepatic disorder is selected from liverinflammation, liver fibrosis, NASH, fatty liver, enlarged liver,alcoholic liver disease, jaundice, cirrhosis, and hepatitis.

In another embodiment, the dyslipidemia disorder is selected fromundesirable blood lipid levels, including low levels of high-densitylipoprotein, high levels of low-density lipoprotein, high levels oftriglycerides, and a combination thereof.

In another embodiment, the cardiovascular disorder is selected fromatherosclerosis, hypertension, stroke and heart attack.

In another embodiment, the present invention provides a novel method fortreating a co-morbidity of obesity, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention or a pharmaceutically acceptable salt formthereof.

In another embodiment, the co-morbidity is selected from diabetes,dyslipidemias, Metabolic Syndrome, dementia, cardiovascular disease, andhepatic disease.

In another embodiment, the co-morbidity is selected from hypertension;gallbladder disease; gastrointestinal disorders; menstrualirregularities; degenerative arthritis; venous statis ulcers; pulmonaryhypoventilation syndrome; sleep apnea; snoring; coronary artery disease;arterial sclerotic disease; pseudotumor cerebri; accident proneness;increased risks with surgeries; osteoarthritis; high cholesterol; and,increased incidence of malignancies of the ovaries, cervix, uterus,breasts, prostrate, and gallbladder.

In another embodiment, the present invention also provides a method ofpreventing or reversing the deposition of adipose tissue in a mammal bythe administration of a compound of the present invention. By preventingor reversing the deposition of adipose tissue, compound of the presentinvention are expected to reduce the incidence or severity of obesity,thereby reducing the incidence or severity of associated co-morbidities.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides the use of thepresent invention for the manufacture of a medicament for the treatmentof an indication recited herein (e.g., obesity, diabetes, dyslipidemias,cardiovascular disorders, hepatic disorders, and a combination thereof).

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment orembodiments to describe additional embodiments. It is also to beunderstood that each individual element of the embodiments is intendedto be taken individually as its own independent embodiment. Furthermore,any element of an embodiment is meant to be combined with any and allother elements from any embodiment to describe an additional embodiment.

DEFINITIONS

The examples provided in the definitions present in this application arenon-inclusive unless otherwise stated. They include but are not limitedto the recited examples.

The compounds herein described may have asymmetric centers, geometriccenters (e.g., double bond), or both. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated. Compounds of the present invention containing anasymmetrically substituted atom may be isolated in optically active orracemic forms. It is well known in the art how to prepare opticallyactive forms, such as by resolution of racemic forms, by synthesis fromoptically active starting materials, or through use of chiralauxiliaries. Geometric isomers of olefins, C═N double bonds, or othertypes of double bonds may be present in the compounds described herein,and all such stable isomers are included in the present invention.Specifically, cis and trans geometric isomers of the compounds of thepresent invention may also exist and may be isolated as a mixture ofisomers or as separated isomeric forms. All processes used to preparecompounds of the present invention and intermediates made therein areconsidered to be part of the present invention. All tautomers of shownor described compounds are also considered to be part of the presentinvention.

“Alkyl” includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. C₁₋₆alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, and s-pentyl.

“Alkenyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₆ alkenyl includes C₂, C₃, C₄, C₅, andC₆ alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more triple carbon-carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl. C₂₋₆ Alkynyl includes C₂, C₃, C₄, C₅, and C₆alkynyl groups.

“Cycloalkyl” includes the specified number of hydrocarbon atoms in asaturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. C₃₋₈ cycloalkyl includes C₃,C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups.

“Cyclic amine” is a hydrocarbon ring wherein one carbon atom of the ringhas been replaced by a nitrogen atom. The cyclic amine can beunsaturated, partially saturated, or fully saturated. The cyclic aminecan also be bicyclic, tricyclic, and polycyclic. Examples of cyclicamine include pyrrolidine and piperidine.

Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Counterion” is used to represent a small, negatively charged species,such as chloride, bromide, hydroxide, acetate, and sulfate.

The group “C₆H₄” represents a phenylene.

“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 memberedmonocyclic, bicyclic, or tricyclic ring, wherein at least one ring, ifmore than one is present, is aromatic. Examples of aryl includefluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

“Heterocycle” refers to any stable 5, 6, or 7-membered monocyclic orbicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring that issaturated, partially unsaturated, or unsaturated (aromatic), andconsisting of: carbon atoms and 1, 2, 3, or 4 ring heteroatomsindependently selected from the group consisting of N, O and S andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The N group may be N, NH,or N-substituent, depending on the chosen ring and if substituents arerecited. The nitrogen and sulfur heteroatoms may optionally be oxidized(e.g., S, S(O), S(O)₂, and N—O). The heterocyclic ring may be attachedto its pendant group at any heteroatom or carbon atom that results in astable structure. The heterocyclic rings described herein may besubstituted on carbon or on a nitrogen atom if the resulting compound isstable. A nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. Typically, the total number of S and O atoms in the heterocycleis not more than 1. Bridged rings are also included in the definition ofheterocycle. A bridged ring occurs when one or more atoms (i.e., C, O,N, or S) link two non-adjacent carbon or nitrogen atoms. Examples ofbridges include one carbon atom, two carbon atoms, one nitrogen atom,two nitrogen atoms, and a carbon-nitrogen group. It is noted that abridge always converts a monocyclic ring into a trycyclic ring. When aring is bridged, the substituents recited for the ring may also bepresent on the bridge.

“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 memberedmonocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic,and which consists of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, O, and S. If theheteroaryl group is bicyclic or tricyclic, then at least one of the twoor three rings must contain a heteroatom, though both or all three mayeach contain one or more heteroatoms. If the heteroaryl group isbicyclic or tricyclic, then only one of the rings must be aromatic. TheN group may be N, NH, or N-substituent, depending on the chosen ring andif substituents are recited. The nitrogen and sulfur heteroatoms mayoptionally be oxidized (e.g., S, S(O), S(O)₂, and N—O). The heteroarylring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heteroaryl rings describedherein may be substituted on carbon or on a nitrogen atom if theresulting compound is stable.

Examples of heterocycles, including heteroaryl, include acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

“Mammal” and “patient” cover warm blooded mammals that are typicallyunder medical care (e.g., humans and domesticated animals). Examplesinclude feline, canine, equine, bovine, and human, as well as justhuman.

“Treating” or “treatment” covers the treatment of a disease-state in amammal, and includes: (a) preventing the disease-state from occurring ina mammal, in particular, when such mammal is predisposed to thedisease-state but has not yet been diagnosed as having it; (b)inhibiting the disease-state, e.g., arresting it development; and/or (c)relieving the disease-state, e.g., causing regression of the diseasestate until a desired endpoint is reached. Treating also includes theamelioration of a symptom of a disease (e.g., lessen the pain ordiscomfort), wherein such amelioration may or may not be directlyaffecting the disease (e.g., cause, transmission, expression, etc.).

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare useful. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, p 1445, the disclosure of which is hereby incorporated byreference.

“Therapeutically effective amount” includes an amount of a compound ofthe present invention that is effective when administered alone or incombination to treat obesity, diabetes, dyslipidemias, cardiovasculardisorders, hepatic disorders, and a combination or comorbitity thereof,or another indication listed herein. “Therapeutically effective amount”also includes an amount of the combination of compounds claimed that iseffective to treat the desired indication. The combination of compoundscan be a synergistic combination. Synergy, as described, for example, byChou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when theeffect of the compounds when administered in combination is greater thanthe additive effect of the compounds when administered alone as a singleagent. In general, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower cytotoxicity, increased effect, or some other beneficial effect ofthe combination compared with the individual components.

Obesity is defined as having a body mass index (BMI) of 30 or above. Theindex is a measure of an individual's body weight relative to height.BMI is calculated by dividing body weight (in kilograms) by height (inmeters) squared. Normal and healthy body weight is defined as having aBMI between 20 and 24.9. Overweight is defined as having a BMI≧25.Obesity has reached epidemic proportions in the U.S., with 44 millionobese Americans, and an additional eighty million deemed medicallyoverweight.

Obesity is a disease characterized as a condition resulting from theexcess accumulation of adipose tissue, especially adipose tissuelocalized in the abdominal area. It is desirable to treat overweight orobese patients by reducing their amount of adipose tissue, and therebyreducing their overall body weight to within the normal range for theirsex and height. In this way, their risk for co-morbidities such asdiabetes, dyllipidemias, and cardiovascular and hepatic diseases will bereduced. It is also desirable to prevent normal weight individuals fromaccumulating additional, excess adipose tissue, effectively maintainingtheir body weights at a BMI<25, and preventing the development ofco-morbidities. It is also desirable to control obesity, effectivelypreventing overweight and obese individuals from accumulatingadditional, excess adipose tissue, reducing the risk of furtherexacerbating their co-morbidities.

Type 2 Diabetes or Diabetes mellitus type 2 or (formerly callednon-insulin-dependent diabetes mellitus (NIDDM), or adult-onsetdiabetes) is a metabolic disorder that is primarily characterized byinsulin resistance, relative insulin deficiency, and hyperglycemia. TheWorld Health Organization definition of diabetes is for a single raisedglucose reading with symptoms otherwise raised values on two occasions,of either fasting plasma glucose≧7.0 mmol/l (126 mg/dl) or with aGlucose tolerance test: two hours after the oral dose a plasmaglucose≧11.1 mmol/l (200 mg/dl). Type 2 Diabetes is rapidly increasingin the developed world and there is some evidence that this pattern willbe followed in much of the rest of the world in coming years. CDC hascharacterized the increase as an epidemic (Diabetes, Atlanta: Centresfor Disease Control, Atlanta, Report no. 2007-05-24). In addition,whereas this disease used to be seen primarily in adults over age 40 (incontrast to Diabetes mellitus type 1), it is now increasingly seen inchildren and adolescents, an increase thought to be linked to risingrates of obesity in this age group.

Insulin resistance means that body cells do not respond appropriatelywhen insulin is present. Unlike insulin-dependent diabetes mellitus(Type 1), the insulin resistance is generally “post-receptor”, meaningit is a problem with the cells that respond to insulin rather than aproblem with insulin production. Type 2 diabetes is presently of unknownetiology (i.e., origin). About 90-95% of all North American cases ofdiabetes are type 2, and about 20% of the population over the age of 65has diabetes mellitus Type 2 (Nature, 2001, 414, 6865). Diabetes affectsover 150 million people worldwide and this number is expected to doubleby 2025. About 55 percent of type 2 diabetics are obese-chronic obesityleads to increased insulin resistance that can develop into diabetes(Morbidity and Mortality Weekly Report 2008, 53, 1066). Type 2 diabetesis often associated with obesity, hypertension, elevated cholesterol(combined hyperlipidemia), and with the condition often termed Metabolicsyndrome (it is also known as Syndrome X, Reavan's syndrome, or CHAOS).There are several drugs available for Type 2 diabetics, includingmetformin, thiazolidinediones, which increase tissue insulinsensitivity, α-glucosidase inhibitors which interfere with absorption ofsome glucose containing nutrients, and peptide analogs that must beinjected.

Dyslipidemia is the presence of abnormal levels of lipids and/orlipoproteins in the blood. Lipids (fatty molecules) are transported in aprotein capsule, and the density of the lipids and type of proteindetermines the fate of the particle and its influence on metabolism.Lipid and lipoprotein abnormalities are extremely common in the generalpopulation, and are regarded as a highly modifiable risk factor forcardiovascular disease due to the influence of cholesterol, one of themost clinically relevant lipid substances, on atherosclerosis. Inaddition, some forms may predispose to acute pancreatitis.

In western societies, most dyslipidemias are hyperlipidemias; that is,an elevation of lipids in the blood, often due to diet and lifestyle.The prolonged elevation of insulin levels can also lead to dyslipidemia.The most prevalent hyperlipidemias include: hypercholesterolemia,characterized by elevated cholesterol (usually LDL),hypertriglyceridemia, characterized by elevated triglycerides (TGs);hyperlipoproteinemia, characterized by elevated lipoproteins;hyperchylomicronemia, characterized by elevated chylomicrons; andcombined hyperlipidemia, characterized by elevated LDL andtriglycerides. Abnormal decreases in the levels of lipids and/orlipoproteins in the blood also can occur. These includehypocholesterolemia, characterized by lowered cholesterol (usually highdensity lipoprotein, or HDL); and abetalipoproteinemia, characterized bylowered beta lipoproteins.

Dyslipidemia contributes to the development of atherosclerosis. Causesmay be primary (genetic) or secondary. Diagnosis is by measuring plasmalevels of total cholesterol, TGs, and individual lipoproteins. Treatmentis dietary changes, exercise, and lipid-lowering drugs. A linearrelation probably exists between lipid levels and cardiovascular risk,so many people with “normal” cholesterol levels benefit from achievingstill lower levels. Normal and abnormal lipid levels have been definedin the Third Report of the Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol in Adults. National Institutes ofHealth, National Heart, Lung, and Blood Institute, 2001.

The treatment of choice for dyslipidemias is lifestyle change, includingdiet and exercise. Drugs are the next step when lifestyle changes arenot effective. Lipid lowering drugs include statins, nicotinic acid,bile acid sequestrants, fibrates, cholesterol absorption inhibitors, andcombination treatments (e.g., niacin and a statin). These agents are notwithout adverse effects, including flushing and impaired glucosetolerance (nicotinic acid), bloating, nausea, cramping, and constipation(bile acid sequestrants). Bile acid sequestrants may also increase TGs,so their use is contraindicated in patients with hypertriglyceridemia.Fibrates potentiate muscle toxicity when used with statins, and mayincrease LDL in patients with high TGs.

There are many kinds of hepatic (i.e., liver) diseases. Viruses causesome of them, like hepatitis A, hepatitis B and hepatitis C. Others canbe the result of drugs, poisons or drinking too much alcohol. If theliver forms scar tissue because of an illness, it's called cirrhosis.Jaundice, or yellowing of the skin, can be one sign of hepatic disease.Cancer can affect the liver. Hepatic diseases such as hemochromatosiscan be inherited. Additional liver diseases include nonalcoholsteatohepatitis (NASH), alcoholic liver disease, cholangiocarcinoma,hepatic encephalopathy, hepatic failure, liver abscess, liver tumors,liver coagulopathy, glycogen storage diseases, portal hypertension,primary biliary cirrhosis, and primary sclerosing cholangitis.

There are few good treatment options for liver diseases. Optionsincludelifestyle change (including diet and exercise), livertransplantation, and insertion of a transjugular intrahepaticportosystemic shunt that is placed in veins in the middle of the liverto improve blood flow to and from the organ. There are few effectivedrug treatment options for hepatic diseases. Interferon is anFDA-approved drug for the treatment of viral hepatitis. The chimericprotein Hyper-IL-6 dramatically enhances hepatocyte proliferation and iscurrently being evaluated as a pharmacological treatment for liverinjury.

Drugs enter the CNS from the systemic circulation by crossing theblood-brain barrier (BBB). The BBB is a highly specialized ‘gate-keeper’that protects the brain by preventing the entry of many potentiallyharmful substances into the CNS from the systemic circulation. Much isknown about the BBB, and of the physical-chemical properties requiredfor compounds transported across it.

Drugs that do not cross the BBB into the CNS or that are readilyeliminated through transport mechanisms (J. Clin. Invest. 1996, 97,2517) are known in the literature and have low CNS activity due to theirinability to develop brain levels necessary for pharmacological action.The BBB has at least one mechanism to remove drugs prior to theiraccumulation in the CNS. P-Glycoproteins (P-gp) localized in plasmamembrane of the BBB can influence the brain penetration andpharmacological activity of many drugs through translocation acrossmembranes. The lack of accumulation into the brain by some drugs can beexplained by their active removal from the brain by P-gp residing in theBBB. For example, the typical opioid drug loperamide, clinically used asan antidiarrheal, is actively removed from the brain by P-gp, thusexplaining its lack of opiate-like CNS effects. Another example isdomperidone, a dopamine receptor blocker that participates in the P-gptransport (J. Clin. Invest. 1996, 97, 2517). Whereas dopamine receptorblockers that cross the BBB can be used to treat schizophrenia, thereadily-eliminated domperidone can be used to prevent emesis, withoutthe likelihood of producing adverse CNS effects.

In addition to the above compounds, agents possessing structuralcharacteristics that retard or prevent BBB penetration or contribute toparticipation in active elimination processes have been identified invarious classes of therapeutics. These include antihistamines (DrugMetab. Dispos. 2003, 31, 312), beta-adrenergic receptor antagonists(Eur. J. Clin. Pharmacol. 1985, 28, Suppl: 21; Br. J. Clin. Pharmacol.,1981, 11, 549), non-nucleoside reverse transcriptase inhibitors (NNRTIs,J. Pharm. Sci., 1999, 88, 950), and opioid antagonists. This lattergroup has been tested in relation to their activity in thegastrointestinal tract. These peripherally selective opioid antagonistsare described in various US patents as being useful in the treatment ofnon-CNS pathologies in mammals, in particular those of thegastrointestinal tract [see U.S. Pat. No. 5,260,542; U.S. Pat. No.5,434,171; U.S. Pat. No. 5,159,081; and U.S. Pat. No. 5,270,238].

Other types of non-brain penetrant compounds can be prepared through thecreation of a charge within the molecule. Thus, the addition of a methylgroup to the tertiary amine functionality of the drugs scopolamine oratropine, unlike the parent molecules, prevents their passage across theBBB through the presence of a positive charge. However, the newmolecules (methyl-scopolamine and methyl-atropine) retain their fullanticholinergic pharmacological properties. As such, these drugs canalso be used to treat peripheral diseases, without the concern ofadverse CNS effects. The quaternary ammonium compound methylnaltrexoneis also used for the prevention and/or treatment of opioid-inducedgastrointestinal side effects associated with opioid administration (J.Pharmacol. Exp. Ther. 2002, 300, 118).

The discovery that the anti-obesity activity of cannabinoid receptorblockers may in part be mediated by a non-CNS mechanism could make itbeneficial for the compounds of the present invention to be peripherallyrestricted (i.e., have an inability or limited ability to cross the BBB,or be readily eliminated from the brain through active transportsystems). It may be desirable for the compounds of the present inventionto be peripherally restricted, which in turn will result in no or verylimited CNS effects. Compounds that provide peripherally mediatedefficacy in treating obesity, diabetes, dyslipidemias, cardiovasculardisorders, hepatic disorders, a comorbitity thereof, or a combination orshould result in therapeutic agents with greater safety. It can bedesirable that the compounds of the present invention, when administeredin a therapeutically effective amount, have no or very limited CNSeffects. It can also be desirable that the lack of CNS effects is aresult of the compounds of the present invention having minimal brainconcentrations when administered in therapeutically effective amounts.In this context, minimal brain concentrations means levels that are toolow to be therapeutically effective for the treatment of a CNSindication or too low to cause significant or measurable deleterious orundesired side effects, or both.

AVE1625 (Compound I when R₁ and R₂ are 4-chlorophenyl, B is H, A isSO₂CH₃, and R₆ is 3,5-difluorophenyl) is a drug that crosses the BBB andis indicated for the treatment of obesity. It is believed that AVE1625works to treat obesity via a CNS mechanism. Compounds like AVE1625 andcompound AA have been described in U.S. Pat. No. 6,355,631. In compoundAA, one of A or B is a group capable of reducing or limiting the CNSactivity of compound AA, or it exists as a quaternized or N-oxide form.This reduced or limited CNS activity occurs via at least one of A or Bbeing a group, or the quaternized or N-oxide form, that either limitscompound AA's ability to cross the BBB relative to that of AVE1625 orenables it to be actively removed from the brain at a rate greater thanthat of AVE1625. Examples of the amount of compound AA present in thebrain can include (a) from 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92,93, 94, 95, 96, 97, 98, 99, to 100% lower than AVE1625, (b) from 90, 91,92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than AVE1625, and (c) from98, 99, to 100% lower than AVE1625 when administered at the same dosage.

The compounds of the present invention are expected to be cannabinoidreceptor antagonists or inverse agonists (e.g., have activity at ≦10μM). Representative compounds have been tested and shown to be active(e.g., see Tables A, B, and C).

An inverse agonist is a compound that not only blocks the action of theendogenous agonist at the receptor, but also exhibits its own activitywhich is usually the opposite of that shown by the agonist. Inverseagonists are also effective against certain types of receptors (e.g.certain histamine receptors/GABA receptors) that have intrinsic activitywithout the interaction of a ligand upon them (also referred to as‘constitutive activity’).

Most methods of treating obesity are dependent on a significantreduction in energy intake, either by a decrease in food intake (e.g.,sibutramine) or by inhibition of fat absorption (e.g., orlistat). In thepresent invention, adipose tissue may be reduced in the absence of asignificant reduction in food intake. The weight loss, as a result ofthe present invention, comes from the treatment with a compound of thepresent invention, largely independent of, though not totallydissociated from, appetite and food intake. It can be desirable thatadipose tissue loss occurs while food intake is maintained, increased or(a) about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 20% below the normal range of the subject prior to being treatedin accordance with the present invention (i.e., its pre-administrationlevel), (b) about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15%below its pre-administration level, (c) about 1, 2, 3, 4, 5, 6, 7, 8, 9,or 10% below its pre-administration level, or (d) about 1, 2, 3, 4, or5% below its pre-administration level.

In some cases, loss of adipose tissue can be accompanied by aconcomitant loss of lean muscle mass. This is particularly evident incancer patients who show a generalized wasting of body tissues,including adipose tissue and lean muscle mass. In the present invention,however, it can be desirable for body fat to be significantly reduced inthe absence of a significant reduction in lean body mass. Adipose tissueloss comes from treatment with a compound of the present invention,independent of a significant change in lean body mass. Thus, adiposetissue loss can occur while lean body mass is maintained, increased, or(a) is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% belowthe normal range of the subject prior to being treated in accordancewith the present invention (i.e., its pre-administration level), (b) isno more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15%below pre-administration levels, (c) is no more than about 1, 2, 3, 4,5, 6, 7, 8, 9, or 10% below pre-administration levels, or (d) is no morethan about 1, 2, 3, 4, or 5% below pre-administration levels.

In some cases, loss of adipose tissue can be accompanied by aconcomitant loss of water mass. This is particularly evident with dietregimens that promote dehydration. In the present invention, it can bedesirable for body fat to be significantly reduced in the absence of asignificant reduction in water mass. In other words, adipose tissue losscomes from treatment with a compound of the present invention,independent of a significant change in water mass. It can be desirablethat adipose tissue loss occurs while water mass is maintained,increased, or (a) is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, or 30% below the normal range of the subject prior to being treatedin accordance with the present invention (i.e., its pre-administrationlevel), (b) is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, or 15% below pre-administration levels, (c) is no more thanabout 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels,or (d) is no more than about 1, 2, 3, 4, or 5% below pre-administrationlevels.

Sibutramine and orlistat are currently marketed for use in the treatmentof obesity, albeit weight loss is achieved through entirely differentmechanism of action. Sibutramine inhibits the neuronal reuptake ofserotonin and noradrenaline, and orlistat inhibits gut lipase enzymesthat are responsible for breaking down ingested fat.

Cannabinoid receptor blockers can promote weight loss through inhibitionof peripheral cannabinoid receptors, a mechanism entirely different fromappetite suppressants, gut lipase inhibitors, and other agents withsimilar indications (e.g., serotonin agonists, leptin, fatty acidsynthase inhibitors, and monoamine oxidase (MAO) inhibitors).Co-administration of a cannabinoid receptor blocker together with one ormore other agents that are useful for treating the indications describedabove (e.g., obesity, diabetes, dyslipidemias, cardiovascular disorders,hepatic disorders, and a combination thereof) is expected to bebeneficial, by producing, for example, either additive or synergisticeffects. Examples of additional agents include an appetite suppressant,a lipase inhibitor, and a MAO inhibitor (e.g., MAO-B and a combinationof MAO-A/B). Therefore, the present invention provides a method oftreating obesity, diabetes, dyslipidemias, cardiovascular disorders,and/or hepatic disorders, and a combination thereof, comprisingadministering a therapeutically effective amount of a compound of thepresent invention and a second component effective for treating thedesired indication.

Examples of second components include anti-obesity agents, whichinclude, but are not limited to: 1) growth hormone secretagogues; 2)growth hormone secretagogue receptor agonists/antagonists; 3)melanocortin agonists; 4) Mc4r (melanocortin 4 receptor) agonists;5).beta.-3 agonists; 7) 5HT2C (serotonin receptor 2C) agonists; 8)orexin antagonists; 9) melanin concentrating hormone antagonists; 10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists; 11)melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists;12) galanin antagonists; 13) CCK agonists; 14) CCK-A (cholecystokinin-A)agonists; 16) corticotropin-releasing hormone agonists; 17) NPY 5antagonists; 18) NPY 1 antagonists; 19) histamine receptor-3 (H3)modulators; 20) histamine receptor-3 (H3) blockers; 21) β-hydroxysteroid dehydrogenase-1 inhibitors (.beta.-HSD-1); 22) PDE(phosphodiesterase) inhibitors; 23) phosphodiesterase-3B (PDE3B)inhibitors; 24) NE (norepinephrine) transport inhibitors; 25)non-selective serotonin/norepinephrine transport inhibitors, such assibutramine, phentermine, or fenfluramine; 26) ghrelin antagonists; 28)leptin derivatives; 29) BRS3 (bombesin receptor subtype 3) agonists; 30)CNTF (Ciliary neurotrophic factors); 31) CNTF derivatives, such asaxokine (Regeneron); 32) monoamine reuptake inhibitors; 33) UCP-1(uncoupling protein-1), 2, or 3 activators; 34) thyroid hormone .beta.agonists; 35) FAS (fatty acid synthase) inhibitors; 37) DGAT2(diacylglycerol acyltransferase 2) inhibitors; 38) ACC2 (acetyl-CoAcarboxylase-2) inhibitors; 39) glucocorticoid antagonists; 40)acyl-estrogens; 41) lipase inhibitors, such as orlistat (Xenical®); 42)fatty acid transporter inhibitors; 43) dicarboxylate transporterinhibitors; 44) glucose transporter inhibitors; 45) phosphatetransporter inhibitors; 46) serotonin reuptake inhibitors; 47) Metformin(Glucophage®); 48) Topiramate (Topimax®); 49) opiate antagonists such asnaltrexone, 50) the non-selective transport inhibitor bupropion, and/or51) MAO inhibitors.

Examples of MAO inhibitors include Moclobemide; Brofaromine; BW A616U;Ro 41-1049; RS-2232; SR 95191; Harmaline; Harman; Amiflamine; BW1370U87; FLA 688; FLA 788; Bifemelane; Clorgyline; LY 51641; MDL 72,394;5-(4-Benzyloxyphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxadiazol-2-one;5-(4-Arylmethoxyphenyl)-2-(2-cyanoethyl)tetrazoles; Lazabemide; Ro16-6491; Almoxatone; XB308; RS-1636; RS-1653; NW-1015; SL 340026;L-selegiline; Rasagiline; Pargyline; AGN 1135; MDL 72,974; MDL 72,145;MDL 72,638; LY 54761; MD 780236; MD 240931; Bifemelane; Toloxatone;Cimoxatone; Iproniazid; Phenelzine; Nialamide; Phenylhydrazine;1-Phenylcyclopropylamine; Isocarboxazid; and, Tranylcypromine.Additional examples of MAO inhibitors can be found in USPA 2007/0004683;U.S. application Ser. No. 11/445,044; USPA 2007/0015734; and U.S.application Ser. No. 11/424,274.

Examples of diabetes disorders include treating Type 1 diabetes, Type 2diabetes, inadequate glucose tolerance, and insulin resistance.

Examples of second components useful for treating diabetes include (a)insulin sensitizers including (i) PPAR-γ agonists such as the glitazones(e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone),and compounds disclosed in WO97/27857, 97/28115, 97/28137, and 97/27847;and (ii) biguanides such as metformin and phenformin; (b) insulin orinsulin mimetics; (c) sulfonylureas such as tolbutamide and glipizide,or related materials; (d) α-glucosidase inhibitors (e.g., acarbose); (e)cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rivastatin, and other statins), (ii) sequestrants (e.g., cholestyramine,colestipol, and dialkylaminoalkyl derivatives of a cross-linkeddextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof,(iv) PPAR-α agonists (e.g., fenofibric acid derivatives includinggemfibrozil, clofibrate, fenofibrate, and bezafibrate), (v) inhibitorsof cholesterol absorption (e.g., β-sitosterol) and acyl CoA: cholesterolacyltransferase inhibitors (e.g., melinamide), and (vi) probucol; (f)PPAR-α/γ agonists; (g) antiobesity compounds (described previously); (h)ileal bile acid transporter inhibitors; (i) insulin receptor activators,(j) dipeptidyl peptidase IV, or DPP-4 inhibitors (sitagliptin,vildagliptin and other DPP-4 inhibitors (k) exenatide, (l) pramLintide,(m) FBPase inhibitors, (n) glucagon receptor antagonists, (o)glucagon-like peptide-1, and (p) the glucagon-like peptide-1 analogues(liraglutide, and others).

The compounds of the present invention are expected to be CB1 receptorblockers and are expected to be useful for treating diseases mediated bythe CB₁ receptor. The compounds of the present are expected to possessan affinity in vitro for the central and/or peripheral cannabinoidreceptors under the experimental conditions described by Devane et al.,Molecular Pharmacology, 1988, 34, 605-613. The compounds according tothe invention are also expected to possess an affinity for thecannabinoid receptors present on preparations of electrically stimulatedisolated organs. These tests can be performed on guinea-pig ileum and onmouse vas deferens according to Roselt et al., Acta PhysiologicaScandinavia 1975, 94, 142-144, and according to Nicolau et al., Arch.Int. Pharmacodyn, 1978, 236, 131-136.

CB1 receptor affinities can be determined using membrane preparations ofChinese hamster ovary (CHO) cells in which the human cannabinoid CB1receptor is stably transfected (Biochem J. 1991, 279, 129-134) inconjunction with [3H]CP-55,940 as radioligand. After incubation of afreshly prepared cell membrane preparation with the [3H]-radioligand,with or without addition of test compound, separation of bound and freeligand is performed by filtration over glass fiber filters.Radioactivity on the filter is measured by liquid scintillationcounting. The IC₅₀ values can be determined from at least threeindependent measurements.

Formulations and Dosages

In the present invention, the compound(s) of the present invention canbe administered in any convenient manner (e.g., enterally orparenterally). Examples of methods of administration include orally andtransdermally. One skilled in this art is aware that the routes ofadministering the compounds of the present invention may varysignificantly. In addition to other oral administrations, sustainedrelease compositions may be favored. Other acceptable routes may includeinjections (e.g., intravenous, intramuscular, subcutaneous, andintraperitoneal); subdermal implants; and, buccal, sublingual, topical,rectal, vaginal, and intranasal administrations. Bioerodible,non-bioerodible, biodegradable, and non-biodegradable systems ofadministration may also be used. Examples of oral formulations includetablets, coated tablets, hard and soft gelatin capsules, solutions,emulsions, and suspensions.

If a solid composition in the form of tablets is prepared, the mainactive ingredient can be mixed with a pharmaceutical vehicle, examplesof which include silica, starch, lactose, magnesium stearate, and talc.The tablets can be coated with sucrose or another appropriate substanceor they can be treated so as to have a sustained or delayed activity andso as to release a predetermined amount of active ingredientcontinuously. Gelatin capsules can be obtained by mixing the activeingredient with a diluent and incorporating the resulting mixture intosoft or hard gelatin capsules. A syrup or elixir can contain the activeingredient in conjunction with a sweetener, which is typicallycalorie-free, an antiseptic (e.g., methylparaben and/or propylparaben),a flavoring, and an appropriate color. Water-dispersible powders orgranules can contain the active ingredient mixed with dispersants orwetting agents or with suspending agents such as polyvinylpyrrolidone,as well as with sweeteners or taste correctors. Rectal administrationcan be effected using suppositories, which are prepared with bindersmelting at the rectal temperature (e.g., cocoa butter and/orpolyethylene glycols). Parenteral administration can be effected usingaqueous suspensions, isotonic saline solutions, or injectable sterilesolutions, which contain pharmacologically compatible dispersants and/orwetting agents (e.g., propylene glycol and/or polyethylene glycol). Theactive ingredient can also be formulated as microcapsules ormicrospheres, optionally with one or more carriers or additives. Theactive ingredient can also be presented in the form of a complex with acyclodextrin, for example α-, β-, or γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin, and/or methyl-β-cyclodextrin.

The dose of the compound of the present invention administered dailywill vary on an individual basis and to some extent may be determined bythe severity of the disease being treated (e.g., obesity, diabetes,dyslipidemias, cardiovascular disorders, and hepatic disorders). Thedose of the compound of the present invention will also vary dependingon the compound administered. Examples of dosages of compounds of thepresent invention include from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06,0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2,3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,76, 80, 85, 90, 95, to 100 mg/kg of mammal body weight. The compound canbe administered in a single dose or in a number of smaller doses over aperiod of time. The length of time during which the compound isadministered varies on an individual basis, and can continue until thedesired results are achieved (i.e., reduction of body fat, or preventionof a gain in body fat). Therapy could, therefore, last from 1 day toweeks, months, or even years depending upon the subject being treated,the desired results, and how quickly the subject responds to treatmentin accordance with the present invention.

A possible example of a tablet of the present invention is as follows.

Ingredient mg/Tablet Active ingredient 100 Powdered lactose 95 Whitecorn starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10Magnesium stearate 2 Tablet weight 250

A possible example of a capsule of the present invention is as follows.

Ingredient mg/Tablet Active ingredient 50 Crystalline lactose 60Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule fillweight 150

In the above capsule, the active ingredient has a suitable particlesize. The crystalline lactose and the microcrystalline cellulose arehomogeneously mixed with one another, sieved, and thereafter the talcand magnesium stearate are admixed. The final mixture is filled intohard gelatin capsules of suitable size.

A possible example of an injection solution of the present invention isas follows.

Ingredient mg/Tablet Active substance 1.0 mg 1N HCl 20.0 μl acetic acid0.5 mg NaCl 8.0 mg Phenol 10.0 mg 1N NaOH q.s. ad pH 5 H₂O q.s. ad 1 mL

Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis (e.g., seeU.S. Pat. No. 6,355,631; Tetrahedron Letters, 46, 525 (2005)). Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or by variations thereon as appreciated bythose skilled in the art. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

Scheme 1 shows that a solution of 4,4′ dichlorobenzophenone andhydroxylamine hydrochloride in a solvent such as ethanol in the presenceof potassium hydroxide and stirred at room temperature to the refluxtemperature of the solvent for 1-3 hrs can afford the oxime (step a).Reduction of the oxime to the amine can be accomplished using lithiumaluminum hydride in THF solution at reflux (step b) (J. Med. Chem., 885(1973)). Treatment of the amine with epichlorohydrin in a solvent suchas ethanol at reflux should provide the azetidinol (step c) (J.Heterocyclic Chem., 271 (1994)). Oxidation of the alcohol may be carriedout −78° C. by treatment with a solution of DMSO in methylene chloridewhich has been treated with oxalyl chloride for 3 to 7 hours, followedby addition of a teriary amine such as triethyl amine and furtherstirring of the reaction mixture at ambient temperature for 12-24 hours(step d). Reductive amination of the ketone with an amine such as3,5-difluoroaniline can be accomplished with triacetoxyborohydride andacetic acid in methylene chloride solution at ambient temperature over aperiod of 24-48 hours (step e). Treatment of the secondary amine withethyl malonyl chloride in a solvent such as methylene chloride in thepresence of triethyamine at 0° C. to room temperature should afford themalonamide ester (step f). Hydrolysis of the ester using lithiumhydroxide in aqueous THF solution should produce, after acidification,the carboxylic acid (step g), which may be coupled with an amino estersuch as the ethyl ester of alanine in the presence ofisobutylchloroformate (IBCF) and N-methylmorpholine in methylenechloride at 0° C. to room temperature to yield the alanine ester adduct(step h). Hydrolysis of the ester, as above, with LiOH solution shouldafford the acid (step i), and subsequent treatment with IBCF andanhydrous ammonia can give the amide (step j). In like manner, the acidof step g can also be converted to the amide using IBCF and anhydrousammonia (step k).

Scheme 2 shows how the 1-[Bis(4-chlorophenyl)methyl]azetidin-3-ol can betreated with N-[3,5-difluorophenyl)-N-carboethoxymethylsulfonamide) inthe presence of diethyl azodicarboxylate (DEAD) and triphenylphosphinein THF under an inert atmosphere such as argon over a period of about 24hours at room temperature and about 24 hours at the reflux temperatureof the solvent to produce the aminoazetidine sulfonamide (step a).N-[3,5-difluorophenyl)-N-carboethoxymethylsulfonamide may be preparedfrom ethyl chlorosulfonylacetate and 3,5-difluoroaniline in pyridine atambient temperature over a period of 18-24 hours. Ethylchlorosulfonylacetate can be prepared by treatment of ethylthiolglycolate with chlorine gas in aqueous methylene chloride solutionat about 0° C. to ambient temperature (U.S. Pat. No. 6,667,306). Thesulfonamide acid may be produced using lithium hydroxide in aqueous THFsolution, after acidification (step b), and coupling with an amino estersuch as the ethyl ester of phenylalanine in the presence ofisobutylchloroformate (IBCF) and N-methylmorpholine in methylenechloride at 0° C. to room temperature to yield the phenylalanine esteradduct (step c). Hydrolysis of the ester, as above, with LiOH solutionshould afford the acid (step d), and subsequent treatment with IBCF andanhydrous ammonia can give the amide (step e). In like manner, the acidof step b can also be converted to the amide using IBCF and anhydrousammonia (step f).

Scheme 3 shows thatN-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl-N-3,5-difluorophenylaminecan be treated with chlorosulfonylacetyl chloride in THF solution in thepresence of triethylamine at about −40 to −70° C. followed by warming toroom temperature under an inert atmosphere such as argon to afford thechlorosulfonylacetamide (step a). Further treatment of thesulfonylchloride with an amino ester such as valine ethyl ester in asolvent such as methylene chloride containing N-methylmorpholine at 0°C. to room temperature can yield the valine ester adduct (step b).Hydrolysis of the ester, as above, with LiOH solution should afford theacid (step c), and subsequent treatment with IBCF and anhydrous ammoniacan give the amide (step d).

Scheme 4 illustrates howN-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl-N-3,5-difluorophenylaminecan be treated with the t-CBZ-aminoethylsulfonyl chloride in methylenechloride at about 0° C. to room temperature in the presence of a basesuch as pyridine or triethylamine to produce the protected-aminosulfonamide (step a). The protecting group can be removed viahydrogenolysis using a Pd—C catalyst in ethanol in a hydrogen atmosphere(step b). The amino sulfonamide can be converted to the amino acidadduct by coupling with a t-BOC-protected amino acid such as alanine inthe presence of isobutylchloroformate (IBCF) and N-methylmorpholine inmethylene chloride at 0° C. to room temperature to (step c). Removal ofthe protecting group using trifluoroacetic acid in methylene chloridecan afford the primary amino compound (step d), and subsequent treatmentwith ethyl malonyl chloride in dichloromethane in the presence of a basecan give the ester amide which upon hydrolysis, as described above,should afford the carboxylic acid derivative (step e). Alternatively,the deprotected amino compound of step (b) can be acylated with ethylmalonyl chloride in the presence of a base in dichloromethane to yieldthe ester amide (step f). Further treatment with anhydrous ammonia canprovide the carboxamide (step g).

Scheme 5 shows how treatment of methyl 4-chloro-3-methoxy-2-butenoate[Synthesis, 391 (1992)] with excess bis(4-chlorophenyl)amine in asolvent such as acetonitrile at refux for 1-3 hours can produce, aftercooling, and hydrochloride salt formation with anhydrous HCl in ether,the aminoester adduct (step a). Methoxy bromination of this unsaturatedammonium salt with NBS in methanol and subsequent heating with twoequivalents of bis(4-chlorophenyl)amine in methanol for 1-3 hours canafford the bis-methoxy ketal of the azetidine carboxylic ester[Tetrahedron Letters, 525 (2005)] (step b). The ketal can be convertedto the ketone using aqueous acid (step c) and sodium borohydridereduction of the ketone should produce the alcohol (step d). Reactingthe alcohol with N-(3,5-difluorophenyl)methylsulfonamide in anhydrousTHF containing diethyl azodicarboxylate and triphenylphosphine under aninert atmosphere such as argon at ambient to slightly elevatedtemperatures for 16-24 hrs should produce the substituted aminoazetidineafter appropriate column chromatography purification [U.S. Pat. No.6,355,631] (step e). Hydrolysis of the ester using lithium hydroxide inaqueous THF solution at ambient or slightly elevated temperatures canprovide the carboxylic acid (step g). Ammonolysis of the ester withanhydrous ammonia at 0° C. to room temperature can produce thecarboxamide (step f). Coupling of the carboxylic acid with an aminoester such as that of threonine in the presence of isobutylchloroformate(IBCF) and N-methylmorpholine in methylene chloride at 0° C. to roomtemperature can yield the amide ester adduct (step h). Hydrolysis of theester, as above, with LiOH solution should afford the acid (step i).Alternatively, ammonolysis of the ester with anhydrous ammonia at 0° C.to room temperature can produce the threonine carboxamide (step j).

Scheme 6 indicates how 2 treatment ofN-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-one and about one equivalentof glyoxylic acid hydrate in methanol with 5% aqueous sodium hydroxideat 0° C. to room temperature for 4 to 16 hours followed by acidificationwith aqueous acid and heating at reflux for 1-3 hours can produce theunsaturated acid adduct (step a). If this material is treated with zincdust in aqueous acetic acid solution at reflux for 0.5-3 hours, thesaturated carboxymethyl-adduct can be produced (step a, no double bond).Treatment of the acids with isobutylchloroformate (IBCF) andN-methylmorpholine in methylene chloride at 0° C. to room temperaturefollowed by addition of anhydrous ammonia can give the amides (step b).Alternatively the acids can be coupled with amino acid esters, such asalanine (Z═Me), in the presence of IBCF and N-methylmorpholine to affordthe amino ester adducts (step c). Reductive amination of theketo-azetidines with an amine such as 3,5-difluoroaniline can beaccomplished with triacetoxyborohydride and acetic acid in methylenechloride solution at ambient temperature over a period of 24-48 hours(step d). Sulfonylation of the anilines using methanesulfonyl chloridein dichloromethane in the presence of a tertiary amine such as triethylamine at 0° C. to ambient temperature can yield the sulfonamides (stepe). As above, these esters can be converted to the carboxylic acidsusing lithium hydroxide in aqueous THF solution (step f). The carboxylicacids in turn can be converted to the carboxamides using IBCF andanhydrous ammonia (step g).

Scheme 7 shows how treatment ofN-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-one and about one equivalentof glyoxylic acid hydrate in methanol with 5% aqueous sodium hydroxideat 0° C. to room temperature for 4 to 16 hours followed by acidificationwith dilute aqueous acetic acid can produce the hydroxy acid adduct(step a). The acid can be esterified with diazomethane in methanolsolution (step b), and the hydroxy-ester subsequently reacted witht-butyldimethylsilyl (TBDMS) chloride in the presence of imidazole inDMF which can provide the alcohol-protected ester (step c). Hydrolysisof the ester using lithium hydroxide in aqueous THF solution at ambientor slightly elevated temperatures should provide the carboxylic acid(step d). Subsequent treatment of the acid with IBCF and anhydrousammonia can give the amide and removal of the TBDMS-protecting groupusing tetrabutyl ammonium fluoride in THF at about ambient temperatureor above can give the hydroxyl carboxamide (step e). Thehydroxy-protected acid may be coupled with an amino ester such as theethyl ester of valine in the presence of isobutylchloroformate (IBCF)and N-methylmorpholine in methylene chloride at 0° C. to roomtemperature to yield the alanine (Z═Me) ester adduct (step f). Reductiveamination of the ketone with an amine such as 3,5-difluoroaniline can beaccomplished with triacetoxyborohydride and acetic acid in methylenechloride solution at ambient temperature over a period of 24-48 hours(step g). Sulfonylation of the aniline using methanesulfonyl chloride indichloromethane in the presence of a tertiary amine such as triethylamine at 0° C. to ambient temperature should yield the sulfonamide (steph). As above, these esters can be converted to the carboxylic acidsusing lithium hydroxide in aqueous THF solution, and removal of theTBDMS group with tetrabutyl ammonium fluoride in THF at about ambienttemperature or above can give the hydroxy amino acid adduct (step i). Ifthe carboxylic acid (step j) is treated with IBCF and anhydrous ammonia,and the TBDMS-protecting group subsequently removed, the amide can beproduced (step k).

Scheme 8 shows the route wherebyN-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl-N-(3,5-difluorophenyl)methylsulfonamidecan be converted with and alkyl halide such as methyl iodide in asolvent such as methanol or benzene to the quaternary ammonium salt(step a). Alternatively, the aminosulfonamide can oxidized with aperacid such as m-chloroperbenzoic acid in a solvent such adichloromethane to produce the corresponding amine-oxide (step b).

One stereoisomer of a compound of the present invention may be a morepotent cannabinoid receptor antagonist than its counterpart(s). Thus,stereoisomers are included in the present invention. When required,separation of the racemic material can be achieved by HPLC using achiral column [Pirckle W. H. et al., Asymmetric synthesis, Vol. 1,Academic Press (1983)], or by a resolution using a resolving agent suchas described in Wilen, S. H. Tables of Resolving Agents and OpticalResolutions 1972, 308 or using enantiomerically pure acids and bases. Achiral compound of the present invention may also be directlysynthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen,E. Acc. Chem. Res. 2000, 33, 421-431 or using other enantio- anddiastereo-selective reactions and reagents known to one skilled in theart of asymmetric synthesis. The diastereoisomers may be preparedaccording to known conventional methods (crystallization, chromatographyor from chiral precursors).

Examples of stereoisomers include compounds of formula Ia, Ib, Ic, Id,Ie, If, Ig, Ih, Ii, and Ij shown below.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Tables 1-8 show representative examples of the compounds of the presentinvention. Each example in the tables represents an individual speciesof the present invention.

TABLE 1

Number R Z X Y 1 H OEt F F 2 H OH F F 3 H NH₂ F F 4 H NHOH F F 5 CH₃ OEtF F 6 CH₃ OH F F 7 CH₃ NH₂ F F 8 CH₃ NHOH F F 9 CH₂C₆H₅ OEt F F 10CH₂C₆H₅ OH F F 11 CH₂C₆H₅ NH₂ F F 12 CH₂C₆H₅ NHOH F F 13 CH₂OH OEt F F14 CH₂OH OH F F 15 CH₂OH NH₂ F F 16 CH₂OH NHOH F F 17 CH₃ NHCH(CH₃)CO₂EtF F 18 CH₃ NHCH(CH₃)CO₂H F F 19 CH₃ NHCH(CH₃)CONH₂ F F 20 CH₃NHCH(CH₃)CONHOH F F 21 H OEt H OCH₃ 22 H OH H OCH₃ 23 H NH₂ H OCH₃ 24 HNHOH H OCH₃ 25 CH₃ OEt H OCH₃ 26 CH₃ OH H OCH₃ 27 CH₃ NH₂ H OCH₃ 28 CH₃NHOH H OCH₃ 29 CH₂C₆H₅ OEt H OCH₃ 30 CH₂C₆H₅ OH H OCH₃ 31 CH₂C₆H₅ NH₂ HOCH₃ 32 CH₂C₆H₅ NHOH H OCH₃ 33 CH₂OH OEt H OCH₃ 34 CH₂OH OH H OCH₃ 35CH₂OH NH₂ H OCH₃ 36 CH₂OH NHOH H OCH₃ 37 CH₃ NHCH(CH₃)CO₂Et H OCH₃ 38CH₃ NHCH(CH₃)CO₂H H OCH₃ 39 CH₃ NHCH(CH₃)CONH₂ H OCH₃ 40 CH₃NHCH(CH₃)CONHOH H OCH₃ 41 H OEt H OH 42 H OH H OH 43 H NH₂ H OH 44 HNHOH H OH 45 CH₃ OEt H OH 46 CH₃ OH H OH 47 CH₃ NH₂ H OH 48 CH₃ NHOH HOH 49 CH₂C₆H₅ OEt H OH 50 CH₂C₆H₅ OH H OH 51 CH₂C₆H₅ NH₂ H OH 52 CH₂C₆H₅NHOH H OH 53 CH₂OH OEt H OH 54 CH₂OH OH H OH 55 CH₂OH NH₂ H OH 56 CH₂OHNHOH H OH 57 CH₃ NHCH(CH₃)CO₂Et H OH 58 CH₃ NHCH(CH₃)CO₂H H OH 59 CH₃NHCH(CH₃)CONH₂ H OH 60 CH₃ NHCH(CH₃)CONHOH H OH

TABLE 2

Number R Z X Y 1 H OEt F F 2 H OH F F 3 H NH₂ F F 4 H NHOH F F 5 CH₃ OEtF F 6 CH₃ OH F F 7 CH₃ NH₂ F F 8 CH₃ NHOH F F 9 CH₂C₆H₅ OEt F F 10CH₂C₆H₅ OH F F 11 CH₂C₆H₅ NH₂ F F 12 CH₂C₆H₅ NHOH F F 13 CH₂OH OEt F F14 CH₂OH OH F F 15 CH₂OH NH₂ F F 16 CH₂OH NHOH F F 17 CH₃ NHCH(CH₃)CO₂EtF F 18 CH₃ NHCH(CH₃)CO₂H F F 19 CH₃ NHCH(CH₃)CONH₂ F F 20 CH₃NHCH(CH₃)CONHOH F F 21 H OEt H OCH₃ 22 H OH H OCH₃ 23 H NH₂ H OCH₃ 24 HNHOH H OCH₃ 25 CH₃ OEt H OCH₃ 26 CH₃ OH H OCH₃ 27 CH₃ NH₂ H OCH₃ 28 CH₃NHOH H OCH₃ 29 CH₂C₆H₅ OEt H OCH₃ 30 CH₂C₆H₅ OH H OCH₃ 31 CH₂C₆H₅ NH₂ HOCH₃ 32 CH₂C₆H₅ NHOH H OCH₃ 33 CH₂OH OEt H OCH₃ 34 CH₂OH OH H OCH₃ 35CH₂OH NH₂ H OCH₃ 36 CH₂OH NHOH H OCH₃ 37 CH₃ NHCH(CH₃)CO₂Et H OCH₃ 38CH₃ NHCH(CH₃)CO₂H H OCH₃ 39 CH₃ NHCH(CH₃)CONH₂ H OCH₃ 40 CH₃NHCH(CH₃)CONHOH H OCH₃ 41 H OEt H OH 42 H OH H OH 43 H NH₂ H OH 44 HNHOH H OH 45 CH₃ OEt H OH 46 CH₃ OH H OH 47 CH₃ NH₂ H OH 48 CH₃ NHOH HOH 49 CH₂C₆H₅ OEt H OH 50 CH₂C₆H₅ OH H OH 51 CH₂C₆H₅ NH₂ H OH 52 CH₂C₆H₅NHOH H OH 53 CH₂OH OEt H OH 54 CH₂OH OH H OH 55 CH₂OH NH₂ H OH 56 CH₂OHNHOH H OH 57 CH₃ NHCH(CH₃)CO₂Et H OH 58 CH₃ NHCH(CH₃)CO₂H H OH 59 CH₃NHCH(CH₃)CONH₂ H OH 60 CH₃ NHCH(CH₃)CONHOH H OH

TABLE 3

Number R Z X Y 1 H OEt F F 2 H OH F F 3 H NH₂ F F 4 H NHOH F F 5 CH₃ OEtF F 6 CH₃ OH F F 7 CH₃ NH₂ F F 8 CH₃ NHOH F F 9 CH₂C₆H₅ OEt F F 10CH₂C₆H₅ OH F F 11 CH₂C₆H₅ NH₂ F F 12 CH₂C₆H₅ NHOH F F 13 CH₂OH OEt F F14 CH₂OH OH F F 15 CH₂OH NH₂ F F 16 CH₂OH NHOH F F 17 CH₃ NHCH(CH₃)CO₂EtF F 18 CH₃ NHCH(CH₃)CO₂H F F 19 CH₃ NHCH(CH₃)CONH₂ F F 20 CH₃NHCH(CH₃)CONHOH F F 21 H OEt H OCH₃ 22 H OH H OCH₃ 23 H NH₂ H OCH₃ 24 HNHOH H OCH₃ 25 CH₃ OEt H OCH₃ 26 CH₃ OH H OCH₃ 27 CH₃ NH₂ H OCH₃ 28 CH₃NHOH H OCH₃ 29 CH₂C₆H₅ OEt H OCH₃ 30 CH₂C₆H₅ OH H OCH₃ 31 CH₂C₆H₅ NH₂ HOCH₃ 32 CH₂C₆H₅ NHOH H OCH₃ 33 CH₂OH OEt H OCH₃ 34 CH₂OH OH H OCH₃ 35CH₂OH NH₂ H OCH₃ 36 CH₂OH NHOH H OCH₃ 37 CH₃ NHCH(CH₃)CO₂Et H OCH₃ 38CH₃ NHCH(CH₃)CO₂H H OCH₃ 39 CH₃ NHCH(CH₃)CONH₂ H OCH₃ 40 CH₃NHCH(CH₃)CONHOH H OCH₃ 41 H OEt H OH 42 H OH H OH 43 H NH₂ H OH 44 HNHOH H OH 45 CH₃ OEt H OH 46 CH₃ OH H OH 47 CH₃ NH₂ H OH 48 CH₃ NHOH HOH 49 CH₂C₆H₅ OEt H OH 50 CH₂C₆H₅ OH H OH 51 CH₂C₆H₅ NH₂ H OH 52 CH₂C₆H₅NHOH H OH 53 CH₂OH OEt H OH 54 CH₂OH OH H OH 55 CH₂OH NH₂ H OH 56 CH₂OHNHOH H OH 57 CH₃ NHCH(CH₃)CO₂Et H OH 58 CH₃ NHCH(CH₃)CO₂H H OH 59 CH₃NHCH(CH₃)CONH₂ H OH 60 CH₃ NHCH(CH₃)CONHOH H OH

TABLE 4

Number R Z X Y 1 H NH₂ F F 2 H NH₂ H OH 3 H NH₂ H OCH₃ 4 CH₃ NH₂ F F 5CH₃ NH₂ H OH 6 CH₃ NH₂ H OCH₃ 7 CH₂C₆H₅ NH₂ F F 8 CH₂C₆H₅ NH₂ F OH 9CH₂C₆H₅ NH₂ F OCH₃ 10 H NHCOCH₂CO₂Et F F 11 H NHCOCH₂CO₂Et H OH 12 HNHCOCH₂CO₂Et H OCH₃ 13 CH₃ NHCOCH₂CO₂Et F F 14 CH₃ NHCOCH₂CO₂Et H OH 15CH₃ NHCOCH₂CO₂Et H OCH₃ 16 CH₂C₆H₅ NHCOCH₂CO₂Et F F 17 CH₂C₆H₅NHCOCH₂CO₂Et H OH 18 CH₂C₆H₅ NHCOCH₂CO₂Et H OCH₃ 19 H NHCOCH₂CO₂H F F 20H NHCOCH₂CO₂H H OH 21 H NHCOCH₂CO₂H H OCH₃ 22 CH₃ NHCOCH₂CO₂H F F 23 CH₃NHCOCH₂CO₂H H OH 24 CH₃ NHCOCH₂CO₂H H OCH₃ 25 CH₂C₆H₅ NHCOCH₂CO₂H F F 26CH₂C₆H₅ NHCOCH₂CO₂H H OH 27 CH₂C₆H₅ NHCOCH₂CO₂H H OCH₃ 28 H NHCOCH₂CONH₂F F 29 H NHCOCH₂CONH₂ H OH 30 H NHCOCH₂CONH₂ H OCH₃ 31 CH₃ NHCOCH₂CONH₂F F 32 CH₃ NHCOCH₂CONH₂ H OH 33 CH₃ NHCOCH₂CONH₂ H OCH₃ 34 CH₂C₆H₅NHCOCH₂CONH₂ F F 35 CH₂C₆H₅ NHCOCH₂CONH₂ H OH 36 CH₂C₆H₅ NHCOCH₂CONH₂ HOCH₃ 37 H CO₂Et F F 38 H CO₂H F F 39 H CONH₂ F F 40 H CONHOH F F 41 HCO₂Et H OH 42 H CO₂H H OH 43 H CONH₂ H OH 44 H CONHOH H OH 45 H CO₂Et HOCH₃ 46 H CO₂H H OCH₃ 47 H CONH₂ H OCH₃ 48 H CONHOH H OCH₃ 49 HCONHCH₂CO₂Et F F 50 H CONHCH₂CO₂Et H OH 51 H CONHCH₂CO₂Et H OCH₃ 52 HCONHCH₂CO₂H F F 53 H CONHCH₂CO₂H H OH 54 H CONHCH₂CO₂H H OCH₃ 55 HCONHCH₂CONH₂ F F 56 H CONHCH₂CONH₂ H OH 57 H CONHCH₂CONH₂ H OCH₃ 58 HCONHCH(CH₃)CO₂Et F F 59 H CONHCH(CH₃)CO₂Et H OH 60 H CONHCH(CH₃)CO₂Et HOCH₃ 61 H CONHCH(CH₃)CO₂H F F 62 H CONHCH(CH₃)CO₂H H OH 63 HCONHCH(CH₃)CO₂H H OCH₃ 64 H CONHCH(CH₃)CONH₂ F F 65 H CONHCH(CH₃)CONH₂ HOH 66 H CONHCH(CH₃)CONH₂ H OCH₃ 67 H CONHCH(CH₂C₆H₅)CO₂Et F F 68 HCONHCH(CH₂C₆H₅)CO₂Et H OH 69 H CONHCH(CH₂C₆H₅)CO₂Et H OCH₃ 70 HCONHCH(CH₂C₆H₅)CO₂H H F 71 H CONHCH(CH₂C₆H₅)CO₂H H OH 72 HCONHCH(CH₂C₆H₅)CO₂H H OCH₃ 73 H CONHCH(CH₂C₆H₅)CONH₂ H F 74 HCONHCH(CH₂C₆H₅)CONH₂ H OH 75 H CONHCH(CH₂C₆H₅)CONH₂ H OCH₃

TABLE 5

Number Z X Y 1 OEt F F 2 OEt H OH 3 OEt H OCH₃ 4 OH F F 5 OH H OH 6 OH HOCH₃ 7 NH₂ F F 8 NH₂ H OH 9 NH₂ H OCH₃ 10 NHCH(CH₃)CO₂Et F F 11NHCH(CH₃)CO₂Et H OH 12 NHCH(CH₃)CO₂Et H OCH₃ 13 NHCH(CH₃)CO₂H F F 14NHCH(CH₃)CO₂H H OH 15 NHCH(CH₃)CO₂H H OCH₃ 16 NHCH(CH₃)CONH₂ F F 17NHCH(CH₃)CONH₂ H OH 18 NHCH(CH₃)CONH₂ H OCH₃ 19 NHCH(CH₂OH)CO₂Et F F 20NHCH(CH₂OH)CO₂Et H OH 21 NHCH(CH₂OH)CO₂Et H OCH₃ 22 NHCH(CH₂OH)CO₂H F F23 NHCH(CH₂OH)CO₂H H OH 24 NHCH(CH₂OH)CO₂H H OCH₃ 25 NHCH(CH₂OH)CONH₂ FF 26 NHCH(CH₂OH)CONH₂ H OH 27 NHCH(CH₂OH)CONH₂ H OCH₃ 28NHCH(CH₂C₆H₅)CO₂Et F F 29 NHCH(CH₂C₆H₅)CO₂Et H OH 30 NHCH(CH₂C₆H₅)CO₂EtH OCH₃ 31 NHCH(CH₂C₆H₅)CO₂H F F 32 NHCH(CH₂C₆H₅)CO₂H H OH 33NHCH(CH₂C₆H₅)CO₂H H OCH₃ 34 NHCH(CH₂C₆H₅)CONH₂ F F 35 NHCH(CH₂C₆H₅)CONH₂H OH 36 NHCH(CH₂C₆H₅)CONH₂ H OCH₃ 37 NHCH(CH₃)CONHCH₂CO₂Et F F 38NHCH(CH₃)CONHCH₂CO₂Et H OH 39 NHCH(CH₃)CONHCH₂CO₂Et H OCH₃ 40NHCH(CH₃)CONHCH₂CO₂H F F 41 NHCH(CH₃)CONHCH₂CO₂H H OH 42NHCH(CH₃)CONHCH₂CO₂H H OCH₃ 43 NHCH(CH₃)CONHCH₂CONH₂ F F 44NHCH(CH₃)CONHCH₂CONH₂ H OH 45 NHCH(CH₃)CONHCH₂CONH₂ H OCH₃

TABLE 6a

Number Z X Y 1 OEt F F 2 OEt H OH 3 OEt H OCH₃ 4 OH F F 5 OH H OH 6 OH HOCH₃ 7 NH₂ F F 8 NH₂ H OH 9 NH₂ H OCH₃ 10 NHCH(CH₃)CO₂Et F F 11NHCH(CH₃)CO₂Et H OH 12 NHCH(CH₃)CO₂Et H OCH₃ 13 NHCH(CH₃)CO₂H F F 14NHCH(CH₃)CO₂H H OH 15 NHCH(CH₃)CO₂H H OCH₃ 16 NHCH(CH₃)CONH₂ F F 17NHCH(CH₃)CONH₂ H OH 18 NHCH(CH₃)CONH₂ H OCH₃ 19 NHCH(CH₂C₆H₅)CO₂Et F F20 NHCH(CH₂C₆H₅)CO₂Et H OH 21 NHCH(CH₂C₆H₅)CO₂Et H OCH₃ 22NHCH(CH₂C₆H₅)CO₂H F F 23 NHCH(CH₂C₆H₅)CO₂H H OH 24 NHCH(CH₂C₆H₅)CO₂H HOCH₃ 25 NHCH(CH₂C₆H₅)CONH₂ F F 26 NHCH(CH₂C₆H₅CONH₂ H OH 27NHCH(CH₂C₆H₅)CONH₂ H OCH₃ 28 NHCH(CH₃)CONHCH₂CO₂Et F F 29NHCH(CH₃)CONHCH₂CO₂Et H OH 30 NHCH(CH₃)CONHCH₂CO₂Et H OCH₃ 31NHCH(CH₃)CONHCH₂CO₂H F F 32 NHCH(CH₃)CONHCH₂CO₂H H OH 33NHCH(CH₃)CONHCH₂CO₂H H OCH₃ 34 NHCH(CH₃)CONHCH₂CONH₂ F F 35NHCH(CH₃)CONHCH₂CONH₂ H OH 36 NHCH(CH₃)CONHCH₂CONH₂ H OCH₃

TABLE 6b

Number Z X Y 1 OEt F F 2 OEt H OH 3 OEt H OCH₃ 4 OH F F 5 OH H OH 6 OH HOCH₃ 7 NH₂ F F 8 NH₂ H OH 9 NH₂ H OCH₃ 10 NHCH(CH₃)CO₂Et F F 11NHCH(CH₃)CO₂Et H OH 12 NHCH(CH₃)CO₂Et H OCH₃ 13 NHCH(CH₃)CO₂H F F 14NHCH(CH₃)CO₂H H OH 15 NHCH(CH₃)CO₂H H OCH₃ 16 NHCH(CH₃)CONH₂ F F 17NHCH(CH₃)CONH₂ H OH 18 NHCH(CH₃)CONH₂ H OCH₃ 19 NHCH(CH₂C₆H₅)CO₂Et F F20 NHCH(CH₂C₆H₅)CO₂Et H OH 21 NHCH(CH₂C₆H₅)CO₂Et H OCH₃ 22NHCH(CH₂C₆H₅)CO₂H F F 23 NHCH(CH₂C₆H₅)CO₂H H OH 24 NHCH(CH₂C₆H₅)CO₂H HOCH₃ 25 NHCH(CH₂C₆H₅)CONH₂ F F 26 NHCH(CH₂C₆H₅)CONH₂ H OH 27NHCH(CH₂C₆H₅)CONH₂ H OCH₃ 28 NHCH(CH₃)CONHCH₂CO₂Et F F 29NHCH(CH₃)CONHCH₂CO₂Et H OH 30 NHCH(CH₃)CONHCH₂CO₂Et H OCH₃ 31NHCH(CH₃)CONHCH₂CO₂H F F 32 NHCH(CH₃)CONHCH₂CO₂H H OH 33NHCH(CH₃)CONHCH₂CO₂H H OCH₃ 34 NHCH(CH₃)CONHCH₂CONH₂ F F 35NHCH(CH₃)CONHCH₂CONH₂ H OH 36 NHCH(CH₃)CONHCH₂CONH₂ H OCH₃

TABLE 7

Number Z X Y 1 OEt F F 2 OEt H OH 3 OEt H OCH₃ 4 OH F F 5 OH H OH 6 OH HOCH₃ 7 NH₂ F F 8 NH₂ H OH 9 NH₂ H OCH₃ 10 NHCH(CH₃)CO₂Et F F 11NHCH(CH₃)CO₂Et H OH 12 NHCH(CH₃)CO₂Et H OCH₃ 13 NHCH(CH₃)CO₂H F F 14NHCH(CH₃)CO₂H H OH 15 NHCH(CH₃)CO₂H H OCH₃ 16 NHCH(CH₃)CONH₂ F F 17NHCH(CH₃)CONH₂ H OH 18 NHCH(CH₃)CONH₂ H OCH₃ 19 NHCH(CH₂C₆H₅)CO₂Et F F20 NHCH(CH₂C₆H₅)CO₂Et H OH 21 NHCH(CH₂C₆H₅)CO₂Et H OCH₃ 22NHCH(CH₂C₆H₅)CO₂H F F 23 NHCH(CH₂C₆H₅)CO₂H H OH 24 NHCH(CH₂C₆H₅)CO₂H HOCH₃ 25 NHCH(CH₂C₆H₅)CONH₂ F F 26 NHCH(CH₂C₆H₅)CONH₂ H OH 27NHCH(CH₂C₆H₅)CONH₂ H OCH₃ 28 NHCH(CH₃)CONHCH₂CO₂Et F F 29NHCH(CH₃)CONHCH₂CO₂Et H OH 30 NHCH(CH₃)CONHCH₂CO₂Et H OCH₃ 31NHCH(CH₃)CONHCH₂CO₂H F F 32 NHCH(CH₃)CONHCH₂CO₂H H OH 33NHCH(CH₃)CONHCH₂CO₂H H OCH₃ 34 NHCH(CH₃)CONHCH₂CONH₂ F F 35NHCH(CH₃)CONHCH₂CONH₂ H OH 36 NHCH(CH₃)CONHCH₂CONH₂ H OCH₃

TABLE 8

Number R X Y R_(7a) 1 Me F F Br⁻ 2 Me H OH Br⁻ 3 Me H OCH₃ Br⁻ 4CH₂CH═CH₂ F F Br⁻ 5 CH₂CH═CH₂ H OH Br⁻ 6 CH₂CH═CH₂ H OCH₃ Br⁻ 7 CH₂C₆H₅F F Br⁻ 8 CH₂C₆H₅ H OH Br⁻ 9 CH₂C₆H₅ H OCH₃ Br⁻ 10 O⁻ F F absent 11 O⁻ HOH absent 12 O⁻ H OCH₃ absent

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

1. A compound of Formula I or Ia or a stereoisomer or pharmaceuticallyacceptable salt thereof:

wherein: R₁ and R₂ are identical or different, and are selected from: i)phenyl or naphthyl, optionally substituted with 1-4 substituentsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃,COR₃, —CN, CO₂R₃, CONR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆alkylene-S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-OH, and —C₁₋₆alkylene-NR₄R₅; or ii) a heteroaryl optionally substituted with 1-4substituents selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, OH, CF₃,OCF₃, —CN, CO₂R₃, CONR₄R₅, —C₁₋₆ alkylene-NR₄R₅, —S(O)_(p)—C₁₋₆ alkyl,—C₁₋₆ alkylene-S(O)_(p)—C₁₋₆ alkyl, and —C₁₋₆ alkylene-OH; R₃ is H orC₁₋₆ alkyl; R₄ and R₅, which are identical or different, are selectedfrom H, OR₃, C₁₋₆ alkyl, CO₂R₃, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, —C₁₋₆alkylene-OH, —C₁₋₆ alkylene-di-OH, and —C₁₋₆ alkylene-tri-OH;alternatively, R₄ and R₅ together with the nitrogen atom to which theyare attached form a 3-10-membered saturated mono- or bicyclicheterocycle, optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen and being optionally substituted with 1-4groups selected from C₁₋₆ alkyl, COR₃, CO₂R₃, CONHR₃, CSNHC₁₋₆ alkyl,═O, C₁₋₆ alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, NO₂, NH₂, NHCONH₂,NHC(O)C₁₋₆ alkyl, and —CONH₂; R₆, at each occurrence, is independentlyselected from C₁₋₆ alkyl, aryl, C₃₋₈ cycloalkyl, and 5-10 memberedheterocycle consisting of: carbon atoms and 1-4 heteroatoms selectedfrom O, S(O)_(q), and N, each of which is optionally substituted with1-4 groups selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃,OCF₃, COR_(S), —CN, CO₂R₃, and CONR₄R₅; A is selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylene-OH, C₁₋₆ alkoxy, COR_(E), —C₁₋₆alkylene-CO₂R₃, —C₁₋₆ alkylene-NR₄R₅, SO₂R₆, —C₁₋₆ alkylene-SO₂R₆,CO(C₁₋₄ alkylene-Z)NR₄R₅, SO₂(C₁₋₄ alkylene-Z)NR₄R₅, CO(C₁₋₄alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NR₄R₅, CO(C₁₋₄ alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃, CO(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,CO(C₁₋₄ alkylene-Z)CO(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃,CO(C₁₋₄ alkylene-Z)CO(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,CO(C₁₋₄ alkylene-Z)SO₂NR₄R₅, CO(C₁₋₄ alkylene-Z)SO₂NH(C₁₋₄alkylene-Z)CO₂R₃, CO(C₁₋₄ alkylene-Z)SO₂NH(C₁₋₄ alkylene-Z)CONR₄R₅,SO₂(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃, SO₂(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)NR₄R₅, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄ alkylene-Z)CO₂R₃,SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄ alkylene-Z)CONR₄R₅, SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NHCO(CH₂)_(m)CO₂R₃, SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NHCO(CH₂)_(m)CONR₄R₅, SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃, SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅, aryl,—CH₂-aryl, heterocycle, and —CH₂-heterocycle, wherein heterocycle is a5-10 membered heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from O, S(O)_(q), and N; Z is selected from H, OH,C₁₋₆ alkyl, (CH₂)_(m)-cycloalkyl, aryl, (CH₂)_(m)-aryl, —C₁₋₆alkylene-OH, —C₁₋₆ alkylene-CO₂R₃, and —C₁₋₆ alkylene-CONR₄R₅, whereinthe aryl is optionally substituted with 1-4 groups selected fromhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, CO—C₁₋₆ alkyl,—CN, CO₂R₃, and CONR₄R₅; B is selected from H, C₁₋₆ alkyl, —C₁₋₆alkylene-OH, (CH₂)_(m)CO₂R₃, (CH₂)_(m)CONR₄R₅, (CH₂)_(m)SO₂R₆, ═CHCO₂R₃,═CHCONR₄R₅, CHOHCO₂R₃, CHOHCONR₄R₅, (CH₂)_(m)CONH(C₁₋₄alkylene-Z)CO₂R₃,(CH₂)_(m)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)SO₂NR₄R₅,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅,═CHCONH(C₁₋₄alkylene-Z)CO₂R₃, ═CHCONH(C₁₋₄ alkylene-Z)CONR₄R₅,═CHCONH(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃,═CHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,═CHCONH(C₁₋₄alkylene-Z)SO₂NR₄R₅, CHOHCONH(C₁₋₄alkylene-Z)CO₂R₃,CHOHCONH(C₁₋₄alkylene-Z)CONR₄R₅, CHOHCONH(C₁₋₄ alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃, CHOHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,and CHOHCONH(C₁₋₄alkylene-Z)SO₂NR₄R₅, m, at each occurrence, isindependently selected from 0, 1, 2, 3, and 4; p, at each occurrence, isindependently selected from 0, 1, and 2; q, at each occurrence, isindependently selected from 0, 1, and 2; alternatively, the azetidineN-atom can be an N-oxide or quaternary ammonium salt when R₁, R₂, R₃,R₄, R₅, R₆, A, B and Z do not contain a CO₂R₃ group; R₇ is selected fromO⁻, C₁₋₆-alkyl, C₁₋₆-alkenyl, C₁₋₆-alkynyl, and CH₂-aryl, wherein thearyl is optionally substituted with 1-4 groups selected from halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, OCF₃, —CO—C₁₋₆ alkyl, and —CN; providedthat when R₇ is O⁻, X⁻ is absent and when R₇ is other than O⁻, X⁻ is ahalogen; further provided that when B is H, C₁₋₆ alkyl or C₁₋₆alkylene-OH, then A is other than H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylene-OH, C₁₋₆ alkoxy, (CH₂)_(m)CO₂R₃, —C₁₋₆ alkylene-NR₄R₅, SO₂R₆,CO(C₁₋₄alkylene-Z)NR₄R₅, aryl, CH₂-aryl, heterocycle, andCH₂-heterocycle.
 2. A compound according to claim 1, wherein thecompound is of Formula I or a stereoisomer or pharmaceuticallyacceptable salt thereof:

wherein: R₁ and R₂ are identical or different, and are selected from: i)phenyl or naphthyl, optionally substituted with 1-4 substituentsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃,COR₃, —CN, CONR₄R₅, C₁₋₆ alkylene-S(O)_(p)—, C₁₋₆ alkylene-S(O)_(p)—C₁₋₆alkyl, C₁₋₆ alkylene-OH, and —C₁₋₆ alkylene-NR₄R₅; or ii) a heteroaryloptionally substituted with 1-4 substituents selected from halogen, C₁₋₆alkyl, C₁₋₆ alkoxy, OH, CF₃, OCF₃, —CN, CONR₄R₅, —C₁₋₆ alkylene-NR₄R₅,—S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-S(O)_(p)—C₁₋₆ alkyl, and C₁₋₆alkylene-OH; R₃ is H or C₁₋₆ alkyl; R₄ and R₅, which are identical ordifferent, are selected from H, OR₃, C₁₋₆ alkyl, CO₂R₃, —C₁₋₆alkylene-O—C₁₋₆ alkyl, and —C₁₋₆ alkylene-OH; alternatively, R₄ and R₅together with the nitrogen atom to which they are attached form a3-10-membered saturated mono- or bicyclic heterocycle, optionallycontaining another heteroatom selected from oxygen, sulfur and nitrogenand being optionally substituted with 1-4 groups selected from C₁₋₆alkyl, COR₃, CONHC₁₋₆ alkyl, CSNHC₁₋₆ alkyl, ═O, C₁₋₆ alkylene-OH, —C₁₋₆alkylene-O—C₁₋₆ alkyl, NO₂, NH₂, NHCONH₂, NHC(O)C₁₋₆ alkyl, and —CONH₂;R₆, at each occurrence, is independently selected from C₁₋₆ alkyl, aryl,C₃₋₈ cycloalkyl, and a 5-10 membered heterocycle consisting of: carbonatoms and 1-4 heteroatoms selected from O, S(O)_(q), and N, each ofwhich is optionally substituted with 1-4 groups selected from halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, COC₁₋₆ alkyl, —CN, andCONR₄R₅; A is selected from CO(C₁₋₄ alkylene-Z)NR₄R₅, SO₂(C₁₋₄alkylene-Z)NR₄R₅, CO(C₁₋₄ alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NR₄R₅,CO(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃, CO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅, CO(C₁₋₄ alkylene-Z)CO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃, CO(C₁₋₄ alkylene-Z)CO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅, CO(C₁₋₄ alkylene-Z)SO₂NR₄R₅,CO(C₁₋₄ alkylene-Z)SO₂NH(C₁₋₄ alkylene-Z)CO₂R₃, CO(C₁₋₄alkylene-Z)SO₂NH(C₁₋₄ alkylene-Z)CONR₄R₅, SO₂(C₁₋₄ alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃, SO₂(C₁₋₄ alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄ alkylene-Z)NR₄R₅, SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄ alkylene-Z)CO₂R₃, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)CONR₄R₅, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)NHCO(CH₂)_(m)CO₂R₃, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)NHCO(CH₂)_(m)CONR₄R₅, SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CO₂R₃, and SO₂(C₁₋₄ alkylene-Z)NHCO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅, Z is selected from H, C₁₋₆alkyl, (CH₂)_(m)-cycloalkyl, aryl, (CH₂)_(m)-aryl, —C₁₋₆ alkylene-OH,—C₁₋₆ alkylene-CO₂R₃, and —C₁₋₆ alkylene-CONR₄R₅, wherein the aryl isoptionally substituted 1-4 groups selected from halogen, C₁₋₆ alkyl,C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, CO—C₁₋₆ alkyl, —CN, CO₂R₃, and CONR₄R₅;and B is selected from H, C₁₋₆ alkyl, and C₁₋₆ alkylene-OH.
 3. Acompound according to claim 1, wherein the compound is of Formula I or astereoisomer or pharmaceutically acceptable salt thereof:

wherein: R₁ and R₂ are identical or different, and are selected from: i)phenyl or naphthyl, optionally substituted with 1-4 substituentsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃,COR₃, —CN, CONR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-S(O)_(p)—C₁₋₆alkyl, —C₁₋₆ alkylene-OH, and —C₁₋₆ alkylene-NR₄R₅; or ii) a heteroaryloptionally substituted with 1-4 substituents selected from halogen, C₁₋₆alkyl, C₁₋₆ alkoxy, OH, CF₃, OCF₃, —CN, CONR₄R₅, -alkylene-NR₄R₅,—S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-S(O)_(p)—C₁₋₆ alkyl, and —C₁₋₆alkylene-OH; R₃ is H or C₁₋₆ alkyl; R₄ and R₅, which are identical ordifferent, are selected from H, OR₃, C₁₋₆ alkyl, CO₂R₃, —C₁₋₆alkylene-O—C₁₋₆ alkyl, and —C₁₋₆ alkylene-OH; alternatively, R₄ and R₅together with the nitrogen atom to which they are attached form a3-10-membered saturated mono- or bicyclic heterocycle, optionallycontaining another heteroatom selected from oxygen, sulfur and nitrogenand being optionally substituted with 1-4 groups selected from C₁₋₆alkyl, COR₃, CONHC₁₋₆ alkyl, CSNHC₁₋₆ alkyl, ═O, —C₁₋₆ alkylene-OH,—C₁₋₆ alkylene-O—C₁₋₆ alkyl, NO₂, NH₂, NHCONH₂, NHC(O)C₁₋₆ alkyl, andCONH₂; R₆, at each occurrence, is independently selected from C₁₋₆alkyl, aryl, C₃₋₈ cycloalkyl, and a 5-10 membered heterocycle consistingof: carbon atoms and 1-4 heteroatoms selected from O, S(O)_(q), and N,each of which is optionally substituted with 1-4 groups selected fromhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, COC₁₋₆ alkyl, —CN,and CONR₄R₅; A is selected from H, —C₁₋₆ alkylene-OH, C₁₋₆ alkoxy,COR_(E), —C₁₋₆ alkylene-NR₄R₅, C₁₋₆ haloalkyl, SO₂R₆, and —C₁₋₆alkylene-SO₂R₆; Z is selected from H, C₁₋₆ alkyl, (CH₂)_(m)-cycloalkyl,aryl, (CH₂)_(m)-aryl, —C₁₋₆ alkylene-OH, and —C₁₋₆ alkylene-CONR₄R₅,wherein the aryl is optionally substituted with 1-4 groups selected fromhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, CO—C₁₋₆ alkyl,—CN, and CONR₄R₅; and, B is selected from (CH₂)_(m)CO₂R₃,(CH₂)_(m)CONR₄R₅, ═CHCO₂R₃, ═CHCONR₄R₅, CHOHCO₂R₃, CHOHCONR₄R₅,(CH₂)_(m)SO₂R₆, (CH₂)_(m)CONH(C₁₋₄alkylene-Z)CO₂R₃,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONR₄R₅,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)SO₂NR₄R₅,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,(CH₂)_(m)CONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅,═CHCONH(C₁₋₄alkylene-Z)CO₂R₃, ═CHCONH(C₁₋₄alkylene-Z)CONR₄R₅,═CHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,═CHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,═CHCONH(C₁₋₄alkylene-Z)SO₂NR₄R₅, CHOHCONH(C₁₋₄alkylene-Z)CO₂R₃,CHOHCONH(C₁₋₄alkylene-Z)CONR₄R₅,CHOHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CO₂R₃,CHOHCONH(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅, andCHOHCONH(C₁₋₄alkylene-Z)SO₂NR₄R₅.
 4. A compound according to claim 1,wherein the compound is of Formula Ia or a stereoisomer orpharmaceutically acceptable salt thereof:

wherein: R₁ and R₂ are identical or different, and are either i) phenylor naphthyl, optionally substituted with 1-4 substituents selected fromhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, COR₃, —CN,CONR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆ alkylene-S(O)_(p)—C₁₋₆ alkyl, and—C₁₋₆ alkylene-OH; or ii) a heteroaryl optionally substituted with 1-4substituents selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, OH, CF₃,OCF₃, —CN, CONR₄R₅, —C₁₋₆ alkylene-NR₄R₅, —S(O)_(p)—C₁₋₆ alkyl, —C₁₋₆alkylene-S(O)_(p)—C₁₋₆ alkyl, and —C₁₋₆ alkylene-OH; R₃ is H or C₁₋₆alkyl; R₄ and R₅, which are identical or different, are selected from H,OR₃, C₁₋₆ alkyl, CO₂R₃, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, and —C₁₋₆alkylene-OH; alternatively, R₄ and R₅ together with the nitrogen atom towhich they are attached form a 3-10-membered saturated mono- or bicyclicheterocycle, optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen and being optionally substituted with 1-4groups selected from C₁₋₆ alkyl, COR₃, CONHC₁₋₆ alkyl, CSNHC₁₋₆ alkyl,═O, C₁₋₆ alkylene-OH, —C₁₋₆ alkylene-O—C₁₋₆ alkyl, NO₂, NH₂, NHCONH₂,NHC(O)C₁₋₆ alkyl, and —CONH₂; R₆, at each occurrence, is independentlyselected from C₁₋₆ alkyl, aryl, C₃₋₈ cycloalkyl, and a 5-10 memberedheterocycle consisting of: carbon atoms and 1-4 heteroatoms selectedfrom O, S(O)_(q), and N, each of which is optionally substituted with1-4 groups selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃,OCF₃, COC₁₋₆ alkyl, —CN, and CONR₄R₅; A is selected from H, —C₁₋₆alkylene-OH, C₁₋₆ haloalkyl, COR_(E), SO₂R₆, —C₁₋₆ alkylene-SO₂R₆,CO(C₁₋₄alkylene-Z)CONH(C₁₋₄ alkylene-Z)CONR₄R₅,CO(C₁₋₄alkylene-Z)CO(C₁₋₄ alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅,CO(C₁₋₄alkylene-Z)SO₂NR₄R₅,CO(C₁₋₄alkylene-Z)SO₂NH(C₁₋₄alkylene-Z)CONR₄R₅,SO₂(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅,SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄alkylene-Z)CONR₄R₅,SO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄alkylene-Z)NHCO(CH₂)_(m)CONR₄R₅, andSO₂(C₁₋₄alkylene-Z)NHCO(C₁₋₄alkylene-Z)CONH(C₁₋₄alkylene-Z)CONR₄R₅; Z isselected from H, C₁₋₆ alkyl, (CH₂)_(m)—C₃₋₈ cycloalkyl, aryl,(CH₂)_(m)-aryl, —C₁₋₆ alkylene-OH, and C₁₋₆ alkylene-CONR₄R₅, whereinthe aryl is optionally substituted with 1-4 groups selected fromhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CHO, OH, CF₃, OCF₃, CO—C₁₋₆ alkyl,—CN, and CONR₄R₅; B is selected from H, C₁₋₆ alkyl, C₁₋₆ alkylene-OH;and, R₇ is selected from O⁻, C₁₋₆-alkyl, C₁₋₆-alkenyl, C₁₋₆-alkynyl, andCH₂-aryl, wherein the aryl is optionally substituted with 1-4 groupsselected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, OCF₃, —CO—C₁₋₆alkyl, and —CN; provided that when R₇ is O⁻, X⁻ is absent; and, providedthat when R₇ is not O⁻, X⁻ is a halogen.
 5. A compound according toclaim 1, wherein the compound is selected from a compound of Table 1 ora pharmaceutically acceptable salt thereof.
 6. A compound according toclaim 1, wherein the compound is selected from a compound of Table 2 ora pharmaceutically acceptable salt thereof.
 7. A compound according toclaim 1, wherein the compound is selected from a compound of Table 3 ora pharmaceutically acceptable salt thereof
 8. A compound according toclaim 1, wherein the compound is selected from a compound of Table 4 ora pharmaceutically acceptable salt thereof.
 9. A compound according toclaim 1, wherein the compound is selected from a compound of Table 5 ora pharmaceutically acceptable salt thereof.
 10. A compound according toclaim 1, wherein the compound is selected from a compound of Table 6a ora pharmaceutically acceptable salt thereof.
 11. A compound according toclaim 1, wherein the compound is selected from a compound of Table 6b ora pharmaceutically acceptable salt thereof.
 12. A compound according toclaim 1, wherein the compound is selected from a compound of Table 7 ora pharmaceutically acceptable salt thereof.
 13. A compound according toclaim 1, wherein the compound is selected from a compound of Table 8 ora pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition, comprising: a compound according to claim 1 and apharmaceutically acceptable carrier.
 15. A method of treating a disease,comprising: administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of claim 1, wherein the disease isselected from obesity, diabetes, dyslipidemias, cardiovasculardisorders, hepatic disorders, and a combination thereof.
 16. The methodof claim 15, wherein the diabetes disorder is selected from Type 1diabetes, Type 2 diabetes, inadequate glucose tolerance, and insulinresistance.
 17. The method of claim 15, wherein the hepatic disorder isselected from liver inflammation, liver fibrosis, NASH, fatty liver,enlarged liver, alcoholic liver disease, jaundice, cirrhosis, andhepatitis.
 18. The method of claim 15, wherein the dyslipidemia disorderis selected from undesirable blood lipid levels, including low levels ofhigh-density lipoprotein, high levels of low-density lipoprotein, highlevels of triglycerides, and a combination thereof.
 19. The method ofclaim 15, wherein the cardiovascular disorder is selected fromatherosclerosis, hypertension, stroke and heart attack.
 20. A method oftreating a co-morbidity of obesity, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt form thereof.
 21. Themethod of claim 20, wherein the co-morbidity is selected from diabetes,dyslipidemias, Metabolic Syndrome, dementia, a cardiovascular disease,and a hepatic disease.
 22. The method of claim 20, wherein theco-morbidity is selected from hypertension; gallbladder disease;gastrointestinal disorders; menstrual irregularities; degenerativearthritis; venous statis ulcers; pulmonary hypoventilation syndrome;sleep apnea; snoring; coronary artery disease; arterial scleroticdisease; pseudotumor cerebri; accident proneness; increased risks withsurgeries; osteoarthritis; high cholesterol; and, increased incidence ofmalignancies of the ovaries, cervix, uterus, breasts, prostrate, andgallbladder.
 23. A method of treating a disease, comprising:administering to a mammal in need thereof a therapeutically effectiveamount of a. a compound of claim 1, and b. a second therapeutic agent;wherein the disease is selected from obesity, diabetes, dyslipidemias,cardiovascular disorders, hepatic disorders, and a combination thereofand the second therapeutic agent is useful for treating the disease.